Renal Cytochrome P450s and Flavin-Containing Monooxygenases

Potential Roles in Metabolism and Toxicity of 1,3-Butadiene, Trichloroethylene, and Tetrachloroethylene
  • Adnan A. Elfarra
Part of the Methods in Pharmacology and Toxicology book series (MIPT)


It is widely recognized that the kidneys contain several enzymes capable of catalyzing the metabolism of drugs and toxicants to yield chemically reactive metabolites that can cause nephrotoxicity. Reactive metabolites generated in the kidneys, and metabolites translocated to the kidneys via the circulation after being formed in the liver, can also be detoxified in the kidneys. The kinetics of these bioactivation and detoxification reactions, which vary between chemicals and depend on the age, sex, renal cell type, and species involved, are important determinants of nephrotoxicity. This chapter reviews current knowledge and experimental approaches used to investigate the potential roles of renal cytochrome P450s (P450s) and flavin-containing monooxygenases (FMOs) in the metabolism and toxicity of three important industrial chemicals—1,3-butadiene (BD), trichloroethylene (TRI), and tetrachloroethylene (TETRA; also known as perchloroethylene)—as model compounds. The chapter illustrates examples of significant species-, tissue-, and sex-related differences in specific metabolic reactions. Because metabolic differences can be both qualitative and quantitative, depending on the chemical nature of the substrate, extrapolating data from one chemical to another, and among different genders and/or species can lead to inaccurate conclusions.

Key Words

Apoptosis blood urea nitrogen 1,3-butadiene butadiene monoxide cysteine conjugate β-lyase cytochrome P450s diepoxybutane flavin-containing monooxygenases GSH conjugation kidney liver mercapturates National Toxicology Program (NTP) necrosis reactive metabolites renal organic anion transporters species extrapolation sulfoxides target organ toxicity tetrachloroethylene trichloroethylene US Environmental Protection Agency 


  1. 1.
    Lohr JW, Willsky GR, Acara MA. Renal drug metabolism. Pharmacol Rev 1998; 50:107–141.PubMedGoogle Scholar
  2. 2.
    Mugford CA, Kedderis GL. Sex-dependent metabolism of xenobiotics. Drug Metab Rev 1998;30:441–498.PubMedCrossRefGoogle Scholar
  3. 3.
    Lock EA, Reed CJ. Renal xenobiotic metabolism. In: Goldstein RS, ed., Sipes IG McQueen CA, Gandolfi AJ, eds.-in-chief. Comprehensive Toxicology, Vol. 7: Renal Toxicology. New York: Elsevier, 1997:77–97.Google Scholar
  4. 4.
    Elfarra AA. Halogenated hydrocarbons. In: Goldstein RS, ed., Sipes IG, McQueen CA, Gandolfi AJ, eds.-in-chief. Comprehensive Toxicology, Vol. 7: Renal Toxicology. New York: Elsevier, 1997:601–616.Google Scholar
  5. 5.
    US Environmental Protection Agency. Health Assessment of 1,3-butadiene. Washington, DC, 2000.Google Scholar
  6. 6.
    National Toxicology Program. The Ninth Report on Carcinogens, National Toxicology Program, US Department of Health and Human Services, Public Health Services, Research Triangle Park, NC, 2000.Google Scholar
  7. 7.
    Melnick RL, Huff J, Chou BJ, Miller RA. Carcinogenicity of 1,3-butadiene in C57BL/6×C3HF1 mice at low exposure concentrations. Cancer Res 1990;50: 6592–6599.PubMedGoogle Scholar
  8. 8.
    Elfarra AA, Moll TS, Krause RJ, Kemper RA, Selzer RR. Reactive metabolites of 1,3-butadiene: DNA and hemoglobin adduct formation and potential roles in carcinogenicity. In: Dansette PM, Snyder RR, Monles TJ, et al., eds. Biological Reactive Intermediates, VI. New York: Kluwer Academic/Plenum, 2001:93–103.Google Scholar
  9. 9.
    Kemper RA, Krause RJ, Elfarra AA. Metabolism of butadiene monoxide by freshly isolated hepatocytes from mice and rats: different partitioning between oxidative, hydrolytic, and conjugation pathways. Drug Metab Dispos 2001;29:830–836.PubMedGoogle Scholar
  10. 10.
    Krause RJ, Elfarra AA. Oxidation of butadiene monoxide to meso-and (±)-diepoxybutane by cDNA-expressed human cytochrome P450s and by mouse, rat, and human liver microsomes: evidence for preferential hydration of mesodiepoxybutane in rat and human liver microsomes. Arch Biochem Biophys 1997; 337:176–184.PubMedCrossRefGoogle Scholar
  11. 11.
    Thorton-Manning JR, Dahl AR, Bechtold WE, Griffith WC, Henderson RF. Comparison of the disposition of butadiene epoxides in Sprague-Dawley rats and B6C3F1 mice following a single and repeated exposures to 1,3-butadiene via inhalation. Toxicology 1997;123:125–134.CrossRefGoogle Scholar
  12. 12.
    Duescher RJ, Elfarra AA. Human liver microsomes are efficient catalysts of 1,3-butadiene oxidation: evidence for major roles by cytochromes P450 2A6 and 2E1. Arch Biochem Biophys 1994;311:342–349.PubMedCrossRefGoogle Scholar
  13. 13.
    Sharer JE, Duescher RJ, Elfarra AA. Species and tissue differences in the microsomal oxidation of 1,3-butadiene and the glutathione conjugation of butadiene monoxide in mice and rats: possible role in 1,3-butadiene toxicity. Drug Metab Dispos 1992;20:658–664.PubMedGoogle Scholar
  14. 14.
    Krause RJ, Sharer JE, Elfarra AA. Epoxide hydrolase-dependent metabolism of butadiene monoxide to yield 3-butene-1,2-diol in mouse, rat, and human liver. Drug Metab Dispos 1997;25:1013–1015.PubMedGoogle Scholar
  15. 15.
    Krause RJ, Philpot RM, Elfarra AA. Role of cytochrome P450 4B1 in 1,3-butadiene oxidation in lung microsomes of humans, rats, and rabbits. Toxicol Sci (Suppl) 1999;48:411.Google Scholar
  16. 16.
    National Toxicology Program. The Tenth Report on Carcinogens, U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program, Research Triangle Park, NC, 2002.Google Scholar
  17. 17.
    Lash LH, Parker JC. Hepatic and renal toxicities associated with perchloroethylene. Pharmacol Rev 2001;53:177–208.PubMedGoogle Scholar
  18. 18.
    Lash LH, Qian W, Putt DA, et al. Renal toxicity of perchloroethylene and S-(1,2,2-trichlorovinyl)glutathione in rats and mice: sex-and species-dependent differences. Toxicol Appl Pharmacol 2002;179:163–171.Google Scholar
  19. 19.
    Lash LH, Qian W, Putt DA, et al. Renal and hepatic toxicity of trichloroethylene and its glutathione-derived metabolites in rats and mice: sex-, species-, and tissue-dependent differences. J Pharmacol Exp Ther 2001;297:155–164.Google Scholar
  20. 20.
    Lash, LH, Xu Y, Elfarra AA, Duescher RJ, Parker JC. Glutathione-dependent metabolism of trichloroethylene in isolated liver and kidney cells of rats and its role in mitochondrial and cellular toxicity. Drug Metab Dispos 1995;23:846–853.PubMedGoogle Scholar
  21. 21.
    Elfarra AA, Krause RJ, Last AR, Lash, LH, Parker JC. Species-and sex-related differences in metabolism of trichloroethylene to yield chloral and tetrachloroethanol in mouse, rat, and human liver microsomes. Drug Metab Dispos 1998;26:779–785.PubMedGoogle Scholar
  22. 22.
    Cummings BS, Lasker JM, Lash LH. Expression of glutathione-dependent and cytochrome P450s in freshly isolated and primary cultures of proximal tubular cells from human kidneys. J Pharmacol Exp Ther 2000;293:677–685.PubMedGoogle Scholar
  23. 23.
    Lash LH, Fisher JW, Lipscomb JC, Parker JC. Metabolism of trichloroethylene. Environ Hlth Perspect 2000;108:177–200.CrossRefGoogle Scholar
  24. 24.
    Lash LH, Qian W, Putt DA, et al. Glutathione conjugation of trichloroethylene in rats and mice: sex-, species-, and tissue-dependent differences. Drug Metab Dispos 1998;26:12–19.Google Scholar
  25. 25.
    Lash LH, Qian W, Putt DA, et al. Glutathione conjugation of perchloroethylene in rats and mice in vitro: sex-, species-, and tissue-dependent differences. Toxicol Appl Pharmacol 1998;150:49–57.Google Scholar
  26. 26.
    Ripp SL, Overby LH, Philpot RM, Elfarra AA. Oxidation of cysteine S-conjugates by rabbit liver microsomes and cDNA-expressed flavin-containing monooxygenases: studies with S-(1,2-dichlorovinyl)-l-cysteine, S-(1,2,2-trichlorovinyl)-l-cysteine, S-allyl-l-cysteine, and S-benzyl-l-cysteine. Mol Pharmacol 1997;51:507–515.PubMedGoogle Scholar
  27. 27.
    Krause RJ, Lash LH, Elfarra AA. Human kidney flavin-containing monooxygenases and their potential roles in cysteine S-conjugate metabolism and nephrotoxicity. J Pharmacol Exp Ther 2003;304:185–191.PubMedCrossRefGoogle Scholar
  28. 28.
    Sausen PJ, Elfarra AA. Reactivity of cysteine S-conjugate sulfoxides: formation of S-[1-chloro-2-(S-glutathionyl)vinyl]-l-cysteine sulfoxide by the reaction of S-(1,2-dichlorovinyl)-l-cysteine sulfoxide with glutathione. Chem Res Toxicol 1991;4: 655–660.PubMedCrossRefGoogle Scholar
  29. 29.
    Lash LH, Sausen PJ, Duescher RJ, Cooley AJ, Elfarra AA. Roles of cysteine conjugate β-lyase and S-oxidase in nephrotoxicity: studies with S-(1,2-dichlorovinyl)-l-cysteine and S-(1,2-dichlorovinyl)-l-cysteine sulfoxide. J Pharmacol Exp Ther 1994;269:374–383.PubMedGoogle Scholar
  30. 30.
    Lash LH, Putt DA, Hueni, SE, Krause RJ, Elfarra AA. Roles of necrosis, apoptosis, and mitochondrial dysfunction in S-(1,2-dichlorovinyl)-l-cysteine sulfoxide-induced cytotoxicity in primary cultures of human renal proximal tubular cells. J Pharmacol Exp Ther 2003;305:1163–1172.PubMedCrossRefGoogle Scholar
  31. 31.
    Elfarra AA, Laboy JI, Cooley AJ. S-(1,2,2-trichlorovinyl)-l-cysteine sulfoxide is a potent nephrotoxin. Toxicol Sci (Suppl) 1999;48:28.Google Scholar
  32. 32.
    Werner M, Birner G, Dekant W. Sulfoxidation of mercapturic acids derived from tri-and tetrachloroethene by cytochrome P450 3A: a bioactivation reaction in addition to deacetylation and cysteine conjugate β-lyase mediated cleavage. Chem Res Toxicol 1996;9:41–49.PubMedCrossRefGoogle Scholar
  33. 33.
    Krause RJ, Glocke SC, Elfarra AA. Sulfoxides as urinary metabolites of S-allyl-l-cysteine in rats: evidence for the involvement of flavin-containing monooxygenases. Drug Metab Dispos 2002;30:1137–1142.PubMedCrossRefGoogle Scholar
  34. 34.
    Lawton MP, Cashman JR, Cresteil T, et al. A nomenclature for the mammalian flavin-containing monooxygenase gene family based on amino acid sequence identities. Arch Biochem Biophys 1994;308:254–257.Google Scholar
  35. 35.
    Overby LH, Carver GC, Philpot RM. Quantitation and kinetic properties of hepatic microsomal and recombinant flavin-containing monooxygenase 3 and 5 from humans. Chem Biol Interact 1997;106:29–45.PubMedCrossRefGoogle Scholar
  36. 36.
    Cashman JR, Yang Z, Yang L, Wrighton SA. Role of hepatic flavin-containing monooxygenase 3 in drug and chemical metabolism in adult humans. Chem Biol Interact 1995;96:33–46.PubMedCrossRefGoogle Scholar
  37. 37.
    Sausen PJ, Elfarra AA. Cysteine conjugate S-oxidase: characterization of a novel enzymatic activity in rat hepatic and renal microsomes. J Biol Chem 1990;265: 6139–6145.PubMedGoogle Scholar
  38. 38.
    Sausen PJ, Duescher RJ, Elfarra AA. Further characterization and purification of the flavin-dependent S-benzyl-l-cysteine S-oxidase activities of rat liver and kidney microsomes. Mol Pharmacol 1993;43:388–396.PubMedGoogle Scholar
  39. 39.
    Phillips IR, Dolphin CT, Clair P, et al. The molecular biology of the flavin-containing monooxygenases of man. Chem Biol Interact 1995;96:17–32.Google Scholar
  40. 40.
    Itagaki K, Carver GT, Philpot RM. Expression and characterization of a modified flavin-containing monooxygenase 4 from humans. J Biol Chem 1996;271: 20102–20107.PubMedCrossRefGoogle Scholar
  41. 41.
    Lattard V, Longin-Sauvageon C, Benoit E. Cloning, sequencing and tissue distribution of rat flavin-containing monooxygenase 4: two different forms are produced by tissue-specific alternative splicing. Mol Pharmacol 2003;63:253–261.PubMedCrossRefGoogle Scholar
  42. 42.
    Duescher RJ, Lawton MP, Philpot RM, Elfarra AA. Flavin-containing monooxygenase (FMO)-dependent metabolism of methionine and evidence for FMO3 being the major FMO involved in methionine sulfoxidation in rabbit liver and kidney microsomes. J Biol Chem 1994;269:17525–17530.PubMedGoogle Scholar
  43. 43.
    Ripp SL, Itagaki K, Philpot RM, Elfarra AA. Methionine S-oxidation in human and rabbit liver microsomes: evidence for a high-affinity methionine S-oxidase activity that is distinct from flavin-containing monooxygenase 3. Arch Biochem Biophys 1999;367:322–332.PubMedCrossRefGoogle Scholar
  44. 44.
    Krause RJ, Ripp SL, Sausen PJ, Overby LH, Philpot RM, Elfarra AA. Characterization of the methionine S-oxidase activity of rat liver and kidney microsomes: immunochemical and kinetic evidence for FMO3 being the major catalyst. Arch Biochem Biophys 1996;333:109–116.PubMedCrossRefGoogle Scholar
  45. 45.
    Ripp, SL, Itagaki K, Philpot RM, Elfarra AA. Species and sex differences in expression of flavin-containing monooxygenase form 3 in liver and kidney microsomes. Drug Metab Dispos 1999;27:46–52.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2005

Authors and Affiliations

  • Adnan A. Elfarra
    • 1
  1. 1.Department of Comparative BiosciencesUniversity of WisconsinMadison

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