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Fifty Years of Cytochrome P450 Research pp 17–41Cite as

Fifty Years of Progress in Drug Metabolism and Toxicology: What Do We Still Need to Know About Cytochrome P450 Enzymes?

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Abstract

The 50 years following the discovery of the cytochrome P450 system have been years of remarkable progress in the basic science and in its application to important problems, particularly in medicine. This chapter reviews what has been done, at both basic and applied levels. My own views on the still unresolved basic issues are presented, along with some thoughts about opportunities for future development in practical applications.

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References

  • Addya S, Anandatheerthavarada HK, Biswas G, Bhagwat SV, Mullick J, Avadhani NG (1997) Targeting of NH2-terminal-processed microsomal protein to mitochondria: a novel pathway for the biogenesis of hepatic mitochondrial P450mt2. J Cell Biol 139:589–599

    PubMed Central  CAS  PubMed  Google Scholar 

  • Akhtar M, Calder MR, Corina DL, Wright JN (1982) Mechanistic studies on C-19 demethylation in oestrogen biosynthesis. Biochem J 201:569–580

    PubMed Central  CAS  PubMed  Google Scholar 

  • Akhtar M, Corina D, Miller S, Shyadehi AZ, Wright JN (1994) Mechanism of the acyl-carbon cleavage and related reactions catalyzed by multifunctional P-450s: studies on cytochrome P45017α. Biochemistry 33:4410–4418

    CAS  PubMed  Google Scholar 

  • Alvares AP, Schilling G, Levin W, Kuntzman R (1967) Studies on the induction of CO-binding pigments in liver microsomes by phenobarbital and 3-methylcholanthrene. Biochem Biophys Res Commun 29:521–526

    CAS  PubMed  Google Scholar 

  • Ames BN, Durston WE, Yamasaki E, Lee FD (1973) Carcinogens are mutagens: a simple test system combining liver homogenates for activation and bacteria for detection. Proc Natl Acad Sci USA 70:2281–2285

    PubMed Central  CAS  PubMed  Google Scholar 

  • Andersson T, Flockhart DA, Goldstein DB, Huang SM, Kroetz DL, Milos PM, Ratain MJ, Thummel K (2005) Drug-metabolizing enzymes: evidence for clinical utility of pharmacogenomic tests. Clin Pharmacol Ther 78:559–581

    CAS  PubMed  Google Scholar 

  • Aoyama Y, Horiuchi T, Gotoh O, Noshiro M, Yoshida Y (1998) Cyp51-like gene of Mycobacterium tuberculosis actually encodes a P450 similar to eukaryotic CYP51. J Biochem (Tokyo) 124:694–696

    CAS  Google Scholar 

  • Auchus RJ, Lee TC, Miller WL (1998) Cytochrome b 5 augments the 17,20-lyase activity of human P450c17 without direct electron transfer. J Biol Chem 273:3158–3165

    CAS  PubMed  Google Scholar 

  • Ayesh R, Idle JR, Ritchie JC, Crothers MJ, Hetzel MR (1984) Metabolic oxidation phenotypes as markers for susceptibility to lung cancer. Nature (Lond) 312:169–170

    CAS  Google Scholar 

  • Bajpai P, Sangar MC, Tang W, Chowdhury G, Cheng Q, Fang J-K, Martin MV, Guengerich FP, Avadhani NG (2013) Metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by mitochondria-targeted cytochrome P450 2D6: implications for Parkinson’s disease. J Biol Chem 288:4436–4451

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bansal S, Liu C-P, Sepuri NBV, Anandatheerthavarada HK, Guengerich FP, Avadhani NG (2010) Mitochondria-targeted cytochrome P450 2E1 preferentially induces oxidative damage and augments alcohol mediated mitochondrial dysfunction in cultured cells. J Biol Chem 285:24609–24619

    PubMed Central  CAS  PubMed  Google Scholar 

  • Beaune P, Kremers PG, Kaminsky LS, de Graeve J, Guengerich FP (1986) Comparison of monooxygenase activities and cytochrome P-450 isozyme concentrations in human liver microsomes. Drug Metab Dispos 14:437–442

    CAS  PubMed  Google Scholar 

  • Bell-Parikh LC, Guengerich FP (1999) Kinetics of cytochrome P450 2E1-catalyzed oxidation of ethanol to acetic acid via acetaldehyde. J Biol Chem 274:23833–23840

    CAS  PubMed  Google Scholar 

  • Bolt HM, Kappus H, Bolt M (1975) Effect of rifampicin treatment on the metabolism of oestradiol and 17α-ethinyloestradiol by human liver microsomes. Eur J Clin Pharmacol 8:301–307

    CAS  PubMed  Google Scholar 

  • Bridges A, Gruenke L, Chang Y-T, Vakser IA, Loew G, Waskell L (1998) Identification of the binding site on cytochrome P450 2B4 for cytochrome b 5 and cytochrome P450 reductase. J Biol Chem 273:17036–17049

    CAS  PubMed  Google Scholar 

  • Brodie AMH (1985) Aromatase inhibition and its pharmacologic implications. Biochem Pharmacol 34:3213–3219

    CAS  PubMed  Google Scholar 

  • Cheng JB, Motola DL, Mangelsdorf DJ, Russell DW (2003) De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-hydroxylase. J Biol Chem 278:38084–38093

    CAS  PubMed  Google Scholar 

  • Cheng Q, Lamb DC, Kelly SL, Li L, Guengerich FP (2010) Cyclization of a cellular dipentaenone by Streptomyces coelicolor cytochrome P450 154A1 without oxidation reduction. J Am Chem Soc 132:15173–15175

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chowdhury G, Calcutt MW, Guengerich FP (2010) Oxidation of N-nitrosodimethylamine and N-nitrosodiethylamine by human cytochrome P450 2A6: sequential oxidation to carboxylic acids and analysis of reaction steps. J Biol Chem 285:8031–8044

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chowdhury G, Calcutt MW, Nagy LD, Guengerich FP (2012) Oxidation of methyl and ethyl nitrosamines by cytochromes P450 2E1 and 2B1. Biochemistry 51:9995–10007

    PubMed Central  CAS  PubMed  Google Scholar 

  • Coelho PS, Brustad EM, Kannan A, Arnold FH (2013) Olefin cyclopropanation via carbene transfer catalyzed by engineered cytochrome P450 enzymes. Science 339:307–310

    CAS  PubMed  Google Scholar 

  • Conney AH (1982) Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons: G. H. A. Clowes Memorial Lecture. Cancer Res 42:4875–4917

    CAS  PubMed  Google Scholar 

  • Correia MA, Mannering GJ (1973) Reduced diphosphopyridine nucleotide synergism of the reduced triphosphopyridine nucleotide-dependent mixed-function oxidase system of hepatic microsomes. II. Role of the type I drug-binding site of cytochrome P-450. Mol Pharmacol 9:470–485

    CAS  PubMed  Google Scholar 

  • d’Errico A, Taioli E, Chen X, Vineis P (1996) Genetic metabolic polymorphisms and the risk of cancer: a review of the literature. Biomarkers 1:149–173

    PubMed  Google Scholar 

  • Daly AK, Day CP, Aithal GP (2002) CYP2C9 polymorphism and warfarin dose requirements. Br J Clin Pharmacol 53:408–409

    PubMed Central  PubMed  Google Scholar 

  • Davydov DR, Botchkareva AE, Davydova NE, Halpert JR (2005) Resolution of two substrate-binding sites in an engineered cytochrome P450eryf bearing a fluorescent probe. Biophys J 89:418–432

    PubMed Central  CAS  PubMed  Google Scholar 

  • Deng Y, Edin ML, Theken KN, Schuck RN, Flake GP, Kannon MA, DeGraff LM, Lih FB, Foley J, Bradbury JA, Graves JP, Tomer KB, Falck JR, Zeldin DC, Lee CR (2011) Endothelial CYP epoxygenase overexpression and soluble epoxide hydrolase disruption attenuate acute vascular inflammatory responses in mice. FASEB J 25:703–713

    PubMed Central  CAS  PubMed  Google Scholar 

  • DeVore NM, Scott EE (2012) Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001. Nature (Lond) 482:116–119

    CAS  Google Scholar 

  • Diehl H, Schädelin J, Ullrich V (1970) Studies on the kinetics of cytochrome P-450 reduction in rat liver microsomes. Hoppe Seylers Z Physiol Chem 351:1359–1371

    CAS  PubMed  Google Scholar 

  • Distlerath LM, Reilly PEB, Martin MV, Davis GG, Wilkinson GR, Guengerich FP (1985) Purification and characterization of the human liver cytochromes P-450 involved in debrisoquine 4-hydroxylation and phenacetin O-deethylation, two prototypes for genetic polymorphism in oxidative drug metabolism. J Biol Chem 260:9057–9067

    CAS  PubMed  Google Scholar 

  • Edson K, Prasad B, Unadkat JD, Suhara Y, Okano T, Guengerich FP, Rettie AE (2013) Cytochrome P450 dependent catabolism of vitamin K: initiation of ω-hydroxylation of human CYP4F2 and CYP4F11. Biochemistry 52:8276–8285

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ekroos M, Sjögren T (2006) Structural basis for ligand promiscuity in cytochrome P450 3A4. Proc Natl Acad Sci USA 103:13862–13867

    Google Scholar 

  • Estabrook RW, Cooper DY, Rosenthal O (1963) The light reversible carbon monoxide inhibition of the steroid C21-hydroxylase system of the adrenal cortex. Biochem Z 338:741–755

    CAS  PubMed  Google Scholar 

  • Estabrook RW, Franklin MR, Cohen B, Shigamatzu A, Hildebrandt AG (1971) Biochemical and genetic factors influencing drug metabolism. Influence of hepatic microsomal mixed function oxidation reactions on cellular metabolic control. Metabolism 20:187–199

    CAS  PubMed  Google Scholar 

  • Estrada DF, Laurence JS, Scott EE (2013) Substrate-modulated cytochrome P450 17A1 and cytochrome b 5 interactions revealed by NMR. J Biol Chem 288:17008–17018

    PubMed Central  CAS  PubMed  Google Scholar 

  • Evans WE, McLeod HL (2003) Pharmacogenomics–drug disposition, drug targets, and side effects. N Engl J Med 348:538–549

    CAS  PubMed  Google Scholar 

  • Gainer JV, Bellamine A, Dawson EP, Womble KE, Grant SW, Wang Y, Cupples LA, Guo CY, Demissie S, O’Donnell CJ, Brown NJ, Waterman MR, Capdevila JH (2005) Functional variant of CYP4A11 20-hydroxyeicosatetraenoic acid synthase is associated with essential hypertension. Circulation 111:63–69

    CAS  PubMed  Google Scholar 

  • Garcia DA, Hylek E (2009) Warfarin pharmacogenetics. N Engl J Med 360:2474, author reply 2475

    CAS  PubMed  Google Scholar 

  • Garfinkel D (1958) Studies on pig liver microsomes. I. Enzymic and pigment composition of different microsomal fractions. Arch Biochem Biophys 77:493–509

    CAS  PubMed  Google Scholar 

  • Gigon PL, Gram TE, Gillette JR (1969) Studies on the rate of reduction of hepatic microsomal cytochrome P-450 by reduced nicotinamide adenine dinucleotide phosphate: effect of drug substrates. Mol Pharmacol 5:109–122

    CAS  PubMed  Google Scholar 

  • Gillette JR, Brodie BB, La Du BN (1957) The oxidation of drugs by liver microsomes: on the role of TPNH and oxygen. J Pharmacol Exp Ther 119:532–540

    CAS  PubMed  Google Scholar 

  • Gomez A, Ingleman-Sundberg M (2009) Epigenetic and microRNA-dependent control of cytochrome P450 expression: a gap between DNA and protein. Pharmacogenomics 10:1067–1076

    CAS  PubMed  Google Scholar 

  • Gonzalez FJ (2004) Cytochrome P450 humanised mice. Hum Genomics 1:300–306

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gonzalez FJ, Skoda RC, Kimura S, Umeno M, Zanger UM, Nebert DW, Gelboin HV, Hardwick JP, Meyer UA (1988) Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature (Lond) 331:442–446

    CAS  Google Scholar 

  • Gorsky LD, Koop DR, Coon MJ (1984) On the stoichiometry of the oxidase and monooxygenase reactions catalyzed by liver microsomal cytochrome P-450: products of oxygen reduction. J Biol Chem 259:6812–6817

    CAS  PubMed  Google Scholar 

  • Guengerich FP (1988a) Oxidation of 17α-ethynylestradiol by human liver cytochrome P-450. Mol Pharmacol 33:500–508

    CAS  PubMed  Google Scholar 

  • Guengerich FP (1988b) Roles of cytochrome P-450 enzymes in chemical carcinogenesis and cancer chemotherapy. Cancer Res 48:2946–2954

    CAS  PubMed  Google Scholar 

  • Guengerich FP (2001) Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem Res Toxicol 14:611–650

    CAS  PubMed  Google Scholar 

  • Guengerich FP (2002) Cytochrome P450 enzymes in the generation of commercial products. Nat Rev Drug Discov 1:359–366

    CAS  PubMed  Google Scholar 

  • Guengerich FP (2005) Human cytochrome P450 enzymes. In: Ortiz de Montellano PR (ed) Cytochrome P450: structure, mechanism, and biochemistry, 3rd edn. Kluwer Academic/Plenum Press, New York, pp 377–530

    Google Scholar 

  • Guengerich FP (2006) Safety assessment of stable drug metabolites. Chem Res Toxicol 19:1559–1560

    CAS  Google Scholar 

  • Guengerich FP (2013) Kinetic deuterium isotope effects in cytochrome P450 reactions. J Labelled Comp Radiopharm 56:428–431

    CAS  PubMed  Google Scholar 

  • Guengerich FP (2014) Cytochrome P450-mediated drug interactions and cardiovascular toxicity: the Seldane to Allegra transformation. In: Wang J, Urban L (eds) Predictive ADMET: integrated approaches in drug discovery and development. Wiley, New York, Chap. 23, pp 523–534

    Google Scholar 

  • Guengerich FP, Cheng Q (2011) Orphans in the human cytochrome P450 family: approaches to discovering function and relevance to pharmacology. Pharmacol Rev 63:684–699

    PubMed Central  CAS  PubMed  Google Scholar 

  • Guengerich FP, Isin EM (2014) Unusual metabolic reactions and pathways. In: Lee P, Aizawa H, Gau L, Prakash C, Zhong D (eds) The handbook of metabolic pathways of xenobiotics. Wiley, Chichester, UK, pp 147–197.

    Google Scholar 

  • Guengerich FP, Johnson WW (1997) Kinetics of ferric cytochrome P450 reduction by NADPH-cytochrome P450 reductase: rapid reduction in absence of substrate and variations among cytochrome P450 systems. Biochemistry 36:14741–14750

    CAS  PubMed  Google Scholar 

  • Guengerich FP, Munro AW (2013) Unusual cytochromes P450: enzymes and reactions. J Biol Chem 288:17063–17069

    PubMed Central  CAS  PubMed  Google Scholar 

  • Guengerich FP, Shimada T (1991) Oxidation of toxic and carcinogenic chemicals by human cytochrome P-450 enzymes. Chem Res Toxicol 4:391–407

    CAS  PubMed  Google Scholar 

  • Guengerich FP, Kim B-R, Gillam EMJ, Shimada T (1994) Mechanisms of enhancement and inhibition of cytochrome P450 catalytic activity. In: Lechner MC (ed) Proceedings of the 8th international conference on cytochrome P450: biochemistry, biophysics, and molecular biology. John Libbey Eurotext, Paris, pp 97–101

    Google Scholar 

  • Guengerich FP, Sohl CD, Chowdhury G (2011) Multi-step oxidations catalyzed by cytochrome P450 enzymes: processive vs. distributive kinetics and the issue of carbonyl oxidation. Arch Biochem Biophys 507:126–134

    PubMed Central  CAS  PubMed  Google Scholar 

  • Guest EJ, Rowland-Yeo K, Rostami-Hodjegan A, Tucker GT, Houston JB, Galetin A (2011) Assessment of algorithms for predicting drug–drug interactions via inhibition mechanisms: comparison of dynamic and static models. Br J Clin Pharmacol 71:72–87

    PubMed Central  CAS  PubMed  Google Scholar 

  • Guryev OL, Gilep AA, Usanov SA, Estabrook RW (2001) Interaction of apo-cytochrome b 5 with cytochromes P4503A4 and P45017A: relevance of heme transfer reactions. Biochemistry 40:5018–5031

    CAS  PubMed  Google Scholar 

  • Gut J, Catin T, Dayer P, Kronbach T, Zanger U, Meyer UA (1986) Debrisoquine/sparteine-type polymorphism of drug oxidation: purification and characterization of two functionally different human liver cytochrome P-450 isozymes involved in impaired hydroxylation of the prototype substrate bufuralol. J Biol Chem 261:11734–11743

    CAS  PubMed  Google Scholar 

  • Hackett JC, Brueggemeier RW, Hadad CM (2005) The final catalytic step of cytochrome P450 aromatase: a density functional theory study. J Am Chem Soc 127:5224–5237

    CAS  PubMed  Google Scholar 

  • Halling J, Petersen MS, Grandjean P, Weihe P, Brosen K (2008) Genetic predisposition to Parkinson’s disease: CYP2D6 and HFE in the Faroe Islands. Pharmacogenet Genomics 18:209–212

    CAS  PubMed  Google Scholar 

  • Hanson KL, VandenBrink BM, Babu KN, Allen KE, Nelson WL, Kunze KL (2010) Sequential metabolism of secondary alkyl amines to metabolic-intermediate complexes: opposing roles for the secondary hydroxylamine and primary amine metabolites of desipramine, (S)-fluoxetine, and N-desmethyldiltiazem. Drug Metab Dispos 38:963–972

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hara T, Kouno J, Kaku T, Takeuchi T, Kusaka M, Tasaka A, Yamaoka M (2013) Effect of a novel 17,20-lyase inhibitor, orteronel (TAK-700), on androgen synthesis in male rats. J Steroid Biochem Mol Biol 134:80–91

    CAS  PubMed  Google Scholar 

  • Harris N, Cohen S, Filatov M, Ogliaro F, Shaik S (2000) Two-state reactivity in the rebound step of alkane hydroxylation by cytochrome P-450: origins of free radicals with finite lifetimes. Angew Chem Int Ed 39:2003–2007

    CAS  Google Scholar 

  • Henderson CJ, McLaughlin LA, Wolf CR (2013) Evidence that cytochrome b 5 and cytochrome b 5 reductase can act as sole electron donors to the hepatic cytochrome P450 systems. Mol Pharmacol 83:1209–1217

    CAS  PubMed  Google Scholar 

  • Hildebrandt A, Estabrook RW (1971) Evidence for the participation of cytochrome b 5 in hepatic microsomal mixed-function oxidation reactions. Arch Biochem Biophys 143:66–79

    CAS  PubMed  Google Scholar 

  • Hildebrandt A, Remmer H, Estabrook RW (1968) Cytochrome P-450 of liver microsomes: one pigment or many. Biochem Biophys Res Commun 30:607–612

    CAS  PubMed  Google Scholar 

  • Hosea NA, Miller GP, Guengerich FP (2000) Elucidation of distinct binding sites for cytochrome P450 3A4. Biochemistry 39:5929–5939

    CAS  PubMed  Google Scholar 

  • Hughes AL, Powell DW, Bard M, Eckstein J, Barbuch R, Link AJ, Espenshade PJ (2007) DAP1/PGRMC1 binds and regulates cytochrome P450 enzymes. Cell Metab 5:143–149

    CAS  PubMed  Google Scholar 

  • Humphreys WG (2008) Drug metabolism research as an integral part of the drug discovery process. In: Zhang D, Zhu M, Humphreys WG (eds) Drug metabolism in drug design and development. Wiley, Hoboken, Chap. 8, pp 239–260

    Google Scholar 

  • Idle JR, Smith RL (1979) Polymorphisms of oxidation at carbon centers of drugs and their clinical significance. Drug Metab Rev 9:301–317

    CAS  PubMed  Google Scholar 

  • Idle JR, Mahgoub A, Lancaster R, Smith RL (1978) Hypotensive response to debrisoquine and hydroxylation phenotype. Life Sci 22:979–984

    CAS  PubMed  Google Scholar 

  • Isin EM, Guengerich FP (2006) Kinetics and thermodynamics of ligand binding by cytochrome P450 3A4. J Biol Chem 281:9127–9136

    CAS  PubMed  Google Scholar 

  • Isin EM, Guengerich FP (2007) Complex reactions catalyzed by cytochrome P450 enzymes. Biochim Biophys Acta 1770:314–329

    CAS  PubMed  Google Scholar 

  • Ito K, Iwatsubo T, Kanamitsu S, Ueda K, Suzuki H, Sugiyama Y (1998) Prediction of pharmacokinetic alterations caused by drug–drug interactions: metabolic interaction in the liver. Pharmacol Rev 50:387–411

    CAS  PubMed  Google Scholar 

  • Johnston JB, Ouellet H, Ortiz de Montellano PR (2010) Functional redundancy of steroid C26-monooxygenase activity in Mycobacterium tuberculosis revealed by biochemical and genetic analyses. J Biol Chem 285:36352–36360

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kalow W (1962) Pharmacogenetics. Saunders, Philadelphia

    Google Scholar 

  • Katagiri M, Ganguli BN, Gunsalus IC (1968) A soluble cytochrome P450 functional in methylene hydroxylation. J Biol Chem 243:3543–3546

    CAS  PubMed  Google Scholar 

  • Kellerman G, Luyten-Kellerman M, Shaw CR (1973a) Genetic variation of aryl hydrocarbon hydroxylase in human lymphocytes. Am J Hum Genet 25:327–331

    Google Scholar 

  • Kellerman G, Shaw CR, Luyten-Kellerman M (1973b) Aryl hydrocarbon hydroxylase inducibility and bronchogenic carcinoma. N Engl J Med 298:934–937

    Google Scholar 

  • Kinney AJ (2006) Metabolic engineering in plants for human health and nutrition. Curr Opin Biotechnol 17:130–138

    CAS  PubMed  Google Scholar 

  • Klingenberg M (1958) Pigments of rat liver microsomes. Arch Biochem Biophys 75:376–386

    CAS  PubMed  Google Scholar 

  • Kola I, Landis J (2004) Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 3:711–715

    CAS  PubMed  Google Scholar 

  • Lang NP, Butler MA, Massengill J, Lawson M, Stotts RC, Maurer-Jensen M, Kadlubar FF (1994) Rapid metabolic phenotypes for acetyltransferase and cytochrome P4501A2 and putative exposure to food-borne heterocyclic amines increase the risk for colorectal cancer or polyps. Cancer Epidemiol Biom 3:675–682

    CAS  Google Scholar 

  • Lee SST, Buters JTM, Pineau T, Fernandez-Salguero P, Gonzalez FJ (1996) Role of Cyp2e1 in the hepatotoxicity of acetaminophen. J Biol Chem 271:12063–12067

    CAS  PubMed  Google Scholar 

  • Lu AYH, Coon MJ (1968) Role of hemoprotein P-450 in fatty acid ω-hydroxylation in a soluble enzyme system from liver microsomes. J Biol Chem 243:1331–1332

    CAS  PubMed  Google Scholar 

  • Mahgoub A, Idle JR, Dring LG, Lancaster R, Smith RL (1977) Polymorphic hydroxylation of debrisoquine in man. Lancet 2:584–586

    CAS  PubMed  Google Scholar 

  • Mangelsdorf DJ, Evans RM (1995) The RXR heterodimers and orphan receptors. Cell 83:841–850

    CAS  PubMed  Google Scholar 

  • McLean KJ, Sabri M, Marshall KR, Lawson RJ, Lewis DG, Clift D, Balding PR, Dunford AJ, Warman AJ, McVey JP, Quinn AM, Sutcliffe MJ, Scrutton NS, Munro AW (2005) Biodiversity of cytochrome P450 redox systems. Biochem Soc Trans 33:796–801

    CAS  PubMed  Google Scholar 

  • Miller WL, Auchus RJ (2011) The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev 32:81–151

    PubMed Central  CAS  PubMed  Google Scholar 

  • Mizutani M, Sato F (2011) Unusual P450 reactions in plant secondary metabolism. Arch Biochem Biophys 507:194–203

    CAS  PubMed  Google Scholar 

  • Moriguchi T, Motohashi H, Hosoya T, Nakajima O, Takahashi S, Ohsako S, Aoki Y, Nishimura N, Tohyama C, Fujii-Kuriyama Y, Yamamoto M (2003) Distinct response to dioxin in an arylhydrocarbon receptor (Ahr)-humanized mouse. Proc Natl Acad Sci USA 100:5652–5657

    PubMed Central  CAS  PubMed  Google Scholar 

  • Mueller GC, Miller JA (1948) The metabolism of 4-dimethylaminoazobenzene by rat liver homogenates. J Biol Chem 176:535–544

    CAS  PubMed  Google Scholar 

  • Mueller GC, Miller JA (1953) The metabolism of methylated aminoazo dyes. II. Oxidative demethylation by rat liver homogenates. J Biol Chem 202:579–587

    CAS  PubMed  Google Scholar 

  • Mueller EJ, Loida PJ, Sligar SG (1995) Twenty-five years of P450cam research: mechanistic insights into oxygenase catalysis. In: Ortiz de Montellano PR (ed) Cytochrome P450: structure, mechanism, and biochemistry, 2nd edn. Plenum, New York, Chap. 3, pp 83–124

    Google Scholar 

  • Mutoh S, Sobhany M, Moore R, Perera L, Pedersen L, Sueyoshi T, Negishi M (2013) Phenobarbital indirectly activates the constitutive active androstane receptor (CAR) by inhibition of epidermal growth factor receptor signaling. Sci Signal 6:ra31

    PubMed  Google Scholar 

  • Nakagawa K, Holla VR, Wei Y, Wang WH, Gatica A, Wei S, Mei S, Miller CM, Cha DR, Price E Jr, Zent R, Pozzi A, Breyer MD, Guan Y, Falck JR, Waterman MR, Capdevila JH (2006) Salt-sensitive hypertension is associated with dysfunctional Cyp4a10 gene and kidney epithelial sodium channel. J Clin Invest 116:1696–1702

    PubMed Central  CAS  PubMed  Google Scholar 

  • Nebert DW, Russell DW (2002) Clinical importance of the cytochromes P450. Lancet 360:1155–1162

    CAS  PubMed  Google Scholar 

  • Nelson DO, Lorusso DJ, Mannering GJ (1973) Requirement of a soluble protein for maximal activity of the monooxidase system of hepatic microsomes. Biochem Biophys Res Commun 53:995–1001

    CAS  PubMed  Google Scholar 

  • Niranjan BG, Avadhani NG (1980) Activation of aflatoxin B1 by a monooxygenase system localized in rat liver mitochondria. J Biol Chem 255:6575–6578

    CAS  PubMed  Google Scholar 

  • Nishida CR, Lee M, Ortiz de Montellano PR (2010) Efficient hypoxic activation of the anticancer agent AQ4N by CYP2S1 and CYP2W1. Mol Pharmacol 78:497–502

    PubMed Central  CAS  PubMed  Google Scholar 

  • Oates NS, Shah RR, Idle JR, Smith RL (1981) Phenformin-induced lactic acidosis associated with impaired debrisoquine hydroxylation. Lancet 1:837–838

    CAS  PubMed  Google Scholar 

  • Omura T, Sato R (1962) A new cytochrome in liver microsomes. J Biol Chem 237:1375–1376

    CAS  PubMed  Google Scholar 

  • Omura T, Sato R (1964a) The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature. J Biol Chem 239:2370–2378

    CAS  PubMed  Google Scholar 

  • Omura T, Sato R (1964b) The carbon monoxide-binding pigment of liver microsomes. II. Solubilization, purification, and properties. J Biol Chem 239:2379–2385

    CAS  PubMed  Google Scholar 

  • Ortiz de Montellano PR, De Voss JJ (2005) Substrate oxidation by cytochrome P450 enzymes. In: Ortiz de Montellano PR (ed) Cytochrome P450: structure, mechanism, and biochemistry, 3rd edn. Kluwer Academic/Plenum Press, New York, pp 183–245

    Google Scholar 

  • Ortiz de Montellano PR, DeVoss JJ (2002) Oxidizing species in the mechanism of cytochrome P450. Nat Prod Rep 19:477–493

    PubMed  Google Scholar 

  • Peterson JA, Ebel RE, O’Keeffe DH, Matsubara T, Estabrook RW (1976) Temperature dependence of cytochrome P-450 reduction. A model for NADPH-cytochrome P-450 reductase: cytochrome P-450 interaction. J Biol Chem 251:4010–4016

    CAS  PubMed  Google Scholar 

  • Plum LA, DeLuca HF (2010) Vitamin D, disease and therapeutic opportunities. Nat Rev Drug Discov 9:941–955

    CAS  PubMed  Google Scholar 

  • Poulos TL, Finzel BC, Gunsalus IC, Wagner GC, Kraut J (1985) The 2.6-Å crystal structure of Pseudomonas putida cytochrome P-450. J Biol Chem 260:16122–16130

    CAS  PubMed  Google Scholar 

  • Rendic S, Guengerich FP (2012) Contributions of human enzymes in carcinogen metabolism. Chem Res Toxicol 25:1316–1383

    PubMed Central  CAS  PubMed  Google Scholar 

  • Rittle J, Green MT (2010) Cytochrome P450 compound I: capture, characterization, and C–H bond activation kinetics. Science 330:933–937

    CAS  PubMed  Google Scholar 

  • Rostami-Hodjegan A, Lennard MS, Woods HF, Tucker GT (1998) Meta-analysis of studies of the CYP2D6 polymorphism in relation to lung cancer and Parkinson’s disease. Pharmacogenetics 8:227–238

    CAS  PubMed  Google Scholar 

  • Ryan KJ (1958) Conversion of androstenedione to estrone by placental microsomes. Biochim Biophys Acta 27:658–662

    CAS  PubMed  Google Scholar 

  • Savas U, Machemer DE, Hsu MH, Gaynor P, Lasker JM, Tukey RH, Johnson EF (2009) Opposing roles of peroxisome proliferator-activated receptor alpha and growth hormone in the regulation of CYP4A11 expression in a transgenic mouse model. J Biol Chem 284:16541–16552

    PubMed Central  CAS  PubMed  Google Scholar 

  • Schenkman JB, Jansson I (2003) The many roles of cytochrome b 5. Pharmacol Ther 97:139–152

    CAS  PubMed  Google Scholar 

  • Schoch GA, Yano JK, Sansen S, Dansette PM, Stout CD, Johnson EF (2008) Determinants of cytochrome P450 2C8 substrate binding: structures of complexes with montelukast, troglitazone, felodipine, and 9-cis-retinoic acid. J Biol Chem 283:17227–17237

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sen K, Hackett JC (2012) Coupled electron transfer and proton hopping in the final step of CYP19-catalyzed androgen aromatization. Biochemistry 51:3039–3049

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sevrioukova IF, Poulos TL (2012) Structural and mechanistic insights into the interaction of cytochrome P450 3A4 with bromoergocryptine, a type I ligand. J Biol Chem 287:3510–3517

    PubMed Central  CAS  PubMed  Google Scholar 

  • Seward HE, Roujeinikova A, McLean KJ, Munro AW, Leys D (2006) Crystal structure of the Mycobacterium tuberculosis P450 CYP121-fluconazole complex reveals new azole drug-P450 binding mode. J Biol Chem 281:39437–39443

    CAS  PubMed  Google Scholar 

  • Shah RR, Oates NS, Idle JR, Smith RL, Lockhart JDF (1982) Impaired oxidation of debrisoquine in patients with perhexiline neuropathy. Br Med J 284:295–299

    CAS  Google Scholar 

  • Shah MB, Kufareva I, Pascual J, Zhang QH, Stout CD, Halpert JR (2013) A structural snapshot of CYP2B4 in complex with paroxetine provides insights into ligand binding and clusters of conformational states. J Pharmacol Exp Ther 346:113–120

    PubMed Central  CAS  PubMed  Google Scholar 

  • Shaik S, Kumar D, de Visser SP, Altun A, Thiel W (2005) Theoretical perspective on the structure and mechanism of cytochrome P450 enzymes. Chem Rev 105:2279–2328

    CAS  PubMed  Google Scholar 

  • Shiro Y, Fujii M, Iizuka T, Adachi S, Tsukamoto K, Nakahara K, Shoun H (1995) Spectroscopic and kinetic studies on reaction of cytochrome P450nor with nitric oxide: implication for its nitric oxide reduction mechanism. J Biol Chem 270:1617–1623

    CAS  PubMed  Google Scholar 

  • Shou M, Grogan J, Mancewicz JA, Krausz KW, Gonzalez FJ, Gelboin HV, Korzekwa KR (1994) Activation of CYP3A4: evidence for the simultaneous binding of two substrates in a cytochrome P450 active site. Biochemistry 33:6450–6455

    CAS  PubMed  Google Scholar 

  • Siller M, Goyal S, Yoshimoto FK, Xiao Y, Wei S, Guengerich FP (2014) Oxidation of endogenous N-arachidonoylserotonin by human cytochrome P450 2U1. J Biol Chem 289: 10476–10487

    Google Scholar 

  • Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB (2013) Profiling 976 toxcast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol 26:878–895

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sladek NE, Mannering GJ (1969) Induction of drug metabolism. II. Qualitative differences in the microsomal N-demethylating systems stimulated by polycyclic hydrocarbons and by phenobarbital. Mol Pharmacol 5:186–199

    CAS  PubMed  Google Scholar 

  • Sligar SG, Denisov IG (2007) Understanding cooperativity in human P450 mediated drug–drug interactions. Drug Metab Rev 39:567–579

    CAS  PubMed  Google Scholar 

  • Sun P, Antoun J, Lin DH, Yue P, Gotlinger KH, Capdevila J, Wang WH (2012) Cyp2c44 epoxygenase is essential for preventing the renal sodium absorption during increasing dietary potassium intake. Hypertension 59:339–347

    PubMed Central  CAS  PubMed  Google Scholar 

  • Swan GE, Benowitz NL, Lessov CN, Jacob P 3rd, Tyndale RF, Wilhelmsen K (2005) Nicotine metabolism: the impact of CYP2A6 on estimates of additive genetic influence. Pharmacogenet Genomics 15:115–125

    CAS  PubMed  Google Scholar 

  • Tamaki Y, Arai T, Sugimura H, Sasaki T, Honda M, Muroi Y, Matsubara Y, Kanno S, Ishikawa M, Hirasawa N, Hiratsuka M (2011) Association between cancer risk and drug-metabolizing enzyme gene (CYP2A6, CYP2A13, CYP4B1, SULT1A1, GSTM1, AND GSTT1) polymorphisms in cases of lung cancer in Japan. Drug Metab Pharmacokinet 26:516–522

    CAS  PubMed  Google Scholar 

  • Thompson D, Oster G (1996) Use of terfenadine and contraindicated drugs. JAMA 275:1339–1341

    CAS  PubMed  Google Scholar 

  • Tian Z, Cheng Q, Yoshimoto FK, Lei L, Lamb DC, Guengerich FP (2013) Cytochrome P450 107U1 is required for sporulation and antibiotic production in Streptomyces coelicolor. Arch Biochem Biophys 530:101–107

    PubMed Central  CAS  PubMed  Google Scholar 

  • Toide K, Yamazaki H, Nagashima R, Itoh K, Iwano S, Takahashi Y, Watanabe S, Kamataki T (2003) Aryl hydrocarbon hydroxylase represents CYP1B1, and not CYP1A1, in human freshly isolated white cells: trimodal distribution of Japanese population according to induction of CYP1B1 mRNA by environmental dioxins. Cancer Epidemiol Biomarkers Prev 12:219–222

    CAS  PubMed  Google Scholar 

  • Tyson CA, Lipscomb JD, Gunsalus IC (1972) The roles of putidaredoxin and P450cam in methylene hydroxylation. J Biol Chem 247:5777–5784

    CAS  PubMed  Google Scholar 

  • Vaz ADN, Pernecky SJ, Raner GM, Coon MJ (1996) Peroxo-iron and oxenoid-iron species as alternative oxygenating agents in cytochrome P450-catalyzed reactions: switching by threonine-302 to alanine mutagenesis of cytochrome P450 2B4. Proc Natl Acad Sci USA 93:4644–4648

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wang K, Guengerich FP (2012) Oxidation of fluorinated 2-aryl-benzothiazole antitumor molecules by human cytochromes P450 1A1 and 2W1. Deactivation by cytochrome P450 2S1. Chem Res Toxicol 25:1740–1751

    CAS  PubMed  Google Scholar 

  • Waxman DJ, Holloway MG (2009) Sex differences in the expression of hepatic drug metabolizing enzymes. Mol Pharmacol 76:215–228

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wedell A (2011) Molecular genetics of 21-hydroxylase deficiency. Endocr Dev 20:80–87

    CAS  PubMed  Google Scholar 

  • West SB, Levin W, Ryan D, Vore M, Lu AYH (1974) Liver microsomal electron transport systems. II. The involvement of cytochrome b 5 in the NADH-dependent hydroxylation of 3,4-benzpyrene by a reconstituted cytochrome P-448-containing system. Biochem Biophys Res Commun 58:516–522

    CAS  PubMed  Google Scholar 

  • White PC, New MI, Dupont B (1984) HLA-linked congenital adrenal hyperplasia results from a defective gene encoding a cytochrome P-450 specific for steroid 21-hydroxylation. Proc Natl Acad Sci USA 81:7505–7509

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wienkers LC, Heath TG (2005) Predicting in vivo drug interactions from in vitro drug discovery data. Nat Rev Drug Discov 4:825–833

    CAS  PubMed  Google Scholar 

  • Williams SN, Dunham E, Bradfield CA (2005) Induction of cytochrome P450 enzymes. In: Ortiz de Montellano PR (ed) Cytochrome P450: structure, mechanism, and biochemistry, 3rd edn. Kluwer Academic/Plenum, New York, pp 323–346

    Google Scholar 

  • Williams JA, Hyland R, Jones BC, Smith DA, Hurst S, Goosen TC, Peterkin V, Koup JR, Ball SE (2004) Drug–drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCI/AUC) ratios. Drug Metab Dispos 32:1201–1208

    CAS  PubMed  Google Scholar 

  • Wu Z-L, Sohl CD, Shimada T, Guengerich FP (2006) Recombinant enzymes over-expressed in bacteria show broad catalytic specificity of human cytochrome P450 2W1 and limited activity of human cytochrome P450 2S1. Mol Pharmacol 69:2007–2014

    CAS  PubMed  Google Scholar 

  • Xiao Y, Guengerich FP (2012) Metabolomic analysis and identification of a role for the orphan human cytochrome P450 2W1 in selective oxidation of lysophospholipids. J Lipid Res 53:1610–1617

    PubMed Central  CAS  PubMed  Google Scholar 

  • Xiao Y, Shinkyo R, Guengerich FP (2011) Cytochrome P450 2S1 is reduced by NADPH-cytochrome P450 reductase. Drug Metab Dispos 39:944–946

    PubMed Central  PubMed  Google Scholar 

  • Yamazaki H, Johnson WW, Ueng Y-F, Shimada T, Guengerich FP (1996) Lack of electron transfer from cytochrome b 5 in stimulation of catalytic activities of cytochrome P450 3A4: characterization of a reconstituted cytochrome P450 3A4/NADPH-cytochrome P450 reductase system and studies with apo-cytochrome b 5. J Biol Chem 271:27438–27444

    CAS  PubMed  Google Scholar 

  • Yamazaki H, Shimada T, Martin MV, Guengerich FP (2001) Stimulation of cytochrome P450 reactions by apo-cytochrome b 5. Evidence against transfer of heme from cytochrome P450 3A4 to apo-cytochrome b 5 or heme oxygenase. J Biol Chem 276:30885–30891

    CAS  PubMed  Google Scholar 

  • Yamazaki H, Komatsu T, Ohyama K, Nakamura M, Asahi S, Shimada N, Guengerich FP, Nakajima A, Yokoi T (2002) Roles of NADPH-P450 reductase and apo- and holo-cytochrome b 5 on xenobiotic oxidations catalyzed by 12 recombinant human cytochrome P450s expressed in membranes of Escherichia coli. Protein Express Purif 24:329–337

    CAS  Google Scholar 

  • Yang B, Graham L, Dikalov S, Mason RP, Falck JR, Liao JK, Zeldin DC (2001) Overexpression of cytochrome P450 CYP2J2 protects against hypoxia-reoxygenation injury in cultured bovine aortic endothelial cells. Mol Pharmacol 60:310–320

    CAS  PubMed  Google Scholar 

  • Yang Q, Nagano T, Shah Y, Cheung C, Ito S, Gonzalez FJ (2008) The PPARα-humanized mouse: a model to investigate species differences in liver toxicity mediated by PPARα. Toxicol Sci 101:132–139

    PubMed Central  CAS  PubMed  Google Scholar 

  • Yang X, Zhang B, Molony C, Chudin E, Hao K, Zhu J, Gaedigk A, Suver C, Zhong H, Leeder JS, Guengerich FP, Strom SC, Schuetz E, Rushmore TH, Ulrich RG, Slatter JG, Schadt EE, Kasarskis A, Lum PY (2010) Genetic and genomic analysis of cytochrome P450 enzyme activities in human liver. Genome Res 20:1020–1036

    PubMed Central  CAS  PubMed  Google Scholar 

  • Yun C-H, Okerholm RA, Guengerich FP (1993) Oxidation of the antihistaminic drug terfenadine in human liver microsomes: role of cytochrome P450 3A4 in N-dealkylation and C-hydroxylation. Drug Metab Dispos 21:403–409

    CAS  PubMed  Google Scholar 

  • Yun C-H, Kim K-H, Calcutt MW, Guengerich FP (2005) Kinetic analysis of oxidation of coumarins by human cytochrome P450 2A6. J Biol Chem 280:12279–12291

    CAS  PubMed  Google Scholar 

  • Zhang H, Im S-C, Waskell L (2007) Cytochrome b 5 increases the rate of product formation by cytochrome P450 2B4 and competes with cytochrome P450 reductase for a binding site on cytochrome P450 2B4. J Biol Chem 282:29766–29776

    CAS  PubMed  Google Scholar 

  • Zhao B, Guengerich FP, Bellamine A, Lamb DC, Izumikawa M, Funa N, Lei L, Podust LM, Sundamoorthy M, Reddy LM, Kelly SL, Stec D, Voehler M, Falck JR, Moore BS, Shimada T, Waterman MR (2005) Binding of two flaviolin substrate molecules, oxidative coupling, and crystal structure of Streptomyces coelicolor A3(2) cytochrome P450 158A2. J Biol Chem 280:11599–11607

    CAS  PubMed  Google Scholar 

  • Zhao B, Kagawa N, Sundaramoorthy M, Banerjee S, Nagy LD, Guengerich FP, Waterman MR (2012) A three-dimensional structure of steroid 21-hydroxylase (cytochrome P450 21A2) with binary substrate occupancy reveals locations of disease-associated variants. J Biol Chem 287:10613–10622

    PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

I thank Kathleen Trisler for her assistance in preparation of the manuscript. P450 research in this laboratory is currently supported by National Institutes of Health grants R37 CA090426, P01 DK038226, and R01 GM103937.

Finally, this chapter is dedicated to the memory of two of the pioneers in this field, Professors Ronald W. Estabrook and Allan H. Conney. Both died in 2013 (August and September, respectively). Professor Estabrook was involved in critical experiments that established P450 as the terminal oxidase in the microsomal electron transport chain. Professor Conney was involved in the discovery of P450 induction as a graduate student with Professors James and Elizabeth Miller, made important contributions regarding the multiplicity of P450s, and, together with Dr. Donald Jerina, established the bay-region diol epoxide pathway for activation of polycyclic aromatic hydrocarbons and its significance in chemical carcinogenesis.

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  1. Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, 638 Robinson Research Building, 2200 Pierce Avenue, Nashville, TN, 37232-0146, USA

    F. Peter Guengerich

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  1. Showa Pharmaceutical University, Tokyo, Japan

    Hiroshi Yamazaki

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Guengerich, F.P. (2014). Fifty Years of Progress in Drug Metabolism and Toxicology: What Do We Still Need to Know About Cytochrome P450 Enzymes?. In: Yamazaki, H. (eds) Fifty Years of Cytochrome P450 Research. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54992-5_2

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