Skip to main content

Genetic Polymorphism of Drug Metabolism in Humans

  • Chapter
Biological Reactive Intermediates IV

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 283))

Abstract

Drug metabolizing enzymes are of paramount importance in drug detoxification as well as chemical mutagenesis, carcinogenesis and toxicity mediated via metabolic activation. Thus genetically determined differences in the activity of these enzymes can influence individual susceptibility to adverse drug reactions, drug induced diseases and certain types of chemically induced cancers. The genetic polymorphisms of three human drug metabolising enzymes, namely N-acetyltransferase and two cytochrome P450 isozymes (P-450IID6: debrisoquine / sparteine polymorphism, P-450IIC10: mephenytoin polymorphism) have been firmly established. Based on the metabolic handling of certain probe drugs the population can be divided into two phenotypes: the rapid acetylator / extensive metabolizer and slow acetylator / poor metabolizer. These polymorphisms have provided useful tools for the study of the relationship between genetically determined differences in the activity of drug metabolizing enzymes and the risk of adverse drug reactions and certain types of chemically induced diseases and cancers.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

eBook
USD 16.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Similar content being viewed by others

References

  • Al-Dabbagh, S.A., Idle, J.R. and Smith, R.L. (1981). Animal modelling of human polymorphic drug oxidation -the metabolism of debrisoquine and phenacetin in rat inbred strains. J. Pharm. Pharmacol. 33: 161–164.

    Article  CAS  PubMed  Google Scholar 

  • Anders, H.H. and Weber W.W. (1986). N-Acetylation pharmacogenetics: Michaelis Menten constants for arylamine drugs as predictors of their N-acetylation rates in vivo. Drug Metab. Dispos. 14: 382–385.

    Google Scholar 

  • Barbeau, A., Cloutier, T., Roy M., Plasse, L., Paris, S. and Poirier, J. (1985). Ecogenetics of Parkinson’s disease: 4-hydroxylation of debrisoquine. Lancet ii: 1213–1215.

    Google Scholar 

  • Barbeau, A., Roy, M., Cloutier, T., Plasse, L. and Paris, S. (1986). Environmental and genetic factors in the etiology of Parkinson’s disease. Adv. Neurol. 45: 299–306.

    Google Scholar 

  • Biehl, J.P. (1957). Emergence of drug resistance as related to the dosage and metabolism of isoniazid. Trans 16th Conf Chemother Tuberc Washington D.C. US Veterans Adm. Army Navy, 108–113.

    Google Scholar 

  • Bönicke, R. and Reif, W. (1953). Enzymatische Inaktivierung von Isonicotinsäurehydrazid im menschlichen und tierischen Organismus. Arch. Exp. Pathol. Pharmakol. 220: 321–333.

    Google Scholar 

  • Brosen, K. and Gram, L.F. (1989). Clinical significance of the sparteine/debrisoquine oxidation polymorphism. Eur. J. Clin. Pharmacol. 36: 537–547.

    Article  CAS  PubMed  Google Scholar 

  • Caporaso, N., Hayes, R.B., Dosemeci, M., Hoover, R., Ayesh, R., Hetzel, M. Nadidle, J. (1989). Lung cancer risk, occupational exposure, and the debrisoquine metabolic phenotype. Can. Res. 49: 3675–3679.

    CAS  Google Scholar 

  • Chen, Z.R., Somogyi, A.A. and Bochner, F. (1988). Polymorphic 0-demethylation of codeine. Lancet ii: 914–915.

    Google Scholar 

  • Cooper, R.G., Evans, D.A.P. and Whibley, E.J. (1984). Polymorphic hydroxylation of perhexiline maleate in man. J. Med. Genet. 21: 27–33.

    Article  CAS  PubMed  Google Scholar 

  • Dayer, P., Desmeules, J., Leemann, T. and Striberni, R. (1988). Bioactivation of the narcotic drug codeine in human liver is mediated by the polymorphic monooxygenase catalyzing debrisoquine 4-hydroxylation (cytochrome P-450 dbl./bun). Biochem. Biophys. Res. Commun. 152: 411–416.

    Article  CAS  PubMed  Google Scholar 

  • Desmeules, J., Dayer, P., Gascon, M.-P. and Magistris, M. (1989). Impact of genetic and environmental factors on codeine analgesia. Clin. Pharmacol. Ther. 45: 122.

    Google Scholar 

  • Devadatta, S., Gangadharan, P.R.J., Andrews, R.H., Fox, W., Ramakrishnan, C.V., Selhon, J.B. and Veru, S. (1960). Peripheral neuritis due to isoniazid. Bull World Health Org. 23: 587–598.

    CAS  PubMed  Google Scholar 

  • Drayer, D.E. and Reidenberg, D.M. (1977). Clinical consequences of polymorphic acetylation of basic drugs. Clin. Pharmacol. Ther. 22: 251–258.

    CAS  PubMed  Google Scholar 

  • Eichelbaum, M. (1975). Ein neuentdeckter Defekt im Arzneimittelstoffwechsel des Menschen: Die fehlende N-Oxidation des Spartein. Habilitationsschrift. Medizinische Fakultät Rheinischen Friedrich-Wilhelms-Universität Bonn.

    Google Scholar 

  • Eichelbaum, M. and Gross, A.S. (1990). The genetic polymorphism of debrisoquine/sparteine - clinical aspects. Pharmacol. Ther. In press.

    Google Scholar 

  • Eichelbaum, M., Spannbrucker, N., Steincke, B. and Dengler, H.J. (1979). Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Eur. J. Clin. Pharmacol. 16: 183–187.

    Article  CAS  PubMed  Google Scholar 

  • Eichelbaum, M., Bertilsson, L., Uwe, J. and Zekorn, C. (1982a). Polymorphic oxidation of sparteine and debrisoquine: Related pharmacogenetic entities. Clin. Pharmacol. Ther. 31: 184–186.

    CAS  Google Scholar 

  • Eichelbaum, M., Musch, E., Castro-Parra, M. and v. Sassen, W. (1982b). Isoniazid hepatotoxicity in relation to acetylator phenotype and isoniazid metabolism. Br J. Clin. Pharmacol. 14: 575P - 576 P.

    Google Scholar 

  • Eichelbaum, M., Baur, M.P., Dengler, H.J., Osikowska-Evers, B.O., Tieves, G., Zekorn, C. and Rittner, C. (1987). Chromosomal assignment of human cytochrome P-450 (debrisoquine/sparteine type) to chromosome 22. Br J. Clin. Pharmacol. 23: 455–458.

    CAS  PubMed  Google Scholar 

  • Fonne-Pfister, R., Bargetzi, M.J. and Meyer, U.A. (1987). MPTP, the neurotoxin inducing Parkinson’s disease, is a potent competitive inhibitor of human and rat cytochrome P450 isozymes (P450bufl, P450dbl) catalyzing debrisoquine 4- hydroxylation. Biochem. Biophys. Res. Comm. 148: 1144–1150.

    Article  CAS  PubMed  Google Scholar 

  • Fonne-Pfister, R. and Meyer, U.A. (1988). Xenobiotic and endobiotic inhibitors of cytochrome P-450dbl function, the target of the debrisoquine/sparteine type polymorphism. Biochem. Pharmacol. 37: 3829–3835.

    Article  CAS  PubMed  Google Scholar 

  • Ged, C., Umbenauer, D.R., Bellew, T.M., Bork, R.W., Srivastava, P.K., Shinriki, N., Lloyd,R.S. and Guengerich, F.P. (1988). Characterization of cDNAs, mRNAs and proteins related to human liver microsomal cytochrome P-450 S-mephenytoin 4-hydroxylase. Biochemistry 27: 6929–6940.

    CAS  Google Scholar 

  • Gonzalez, F.J. (1989). The molecular biology of cytochrome P-450s. PharmacoL Rev. 40: 243–288.

    Google Scholar 

  • Gonzalez, F.J., Vilbois, F., Hardwick, J.P., McBride, O.W., Nebert, D.W., Gelboin, H.V. and Meyer, U.A. (1988a). Human debrisoquine 4-hydroxylase (P450IID1): cDNA and deduced amino acid sequence and assignment of the CYP2D locus to chromosome 22. Genomics 2: 174–179.

    Google Scholar 

  • Gonzalez, F.J., Skoda, R.C., Kimura, S., Umeno, M., Zanger, U.M., Nebert, D.W., Gelboin, H.V., Hardwick, J.P. and Meyer, U.A. (1988b). Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature (Lond) 331: 442–446.

    Article  CAS  Google Scholar 

  • Grant, D.M., Tang, B.K. and Kalow, W. (1984). Polymorphic N-acetylation of a caffeine metabolite. Clin. Pharmacol. Ther. 33: 355–359.

    Article  Google Scholar 

  • Grant, D.M., Lottspeich, F. and Meyer, U.A. (1989a). Evidence for two closely related isozymes of arylamine N-acetyltransferase in human liver. FEBS Letters 244: 203–207.

    Article  CAS  PubMed  Google Scholar 

  • Grant, D.M., Eichelbaum, M. and Meyer, U.A. (1989b). Genetic polymorphism of Nacetyltransferase: enzyme activity and content in liver biopsies correlates with acetylator phenotype determined with caffeine. Eur. J. Clin. Pharmacol. 36: 199.

    Article  Google Scholar 

  • Grant, D.M., Blum, M., Demierre, A. and Meyer, U.A. (1989c). Nucleotide sequence for an intronless gene for a human arylamine N-acetyltransferases related to polymorphic drug acetylation. Nucleic Acids Res. 17: 3978.

    CAS  Google Scholar 

  • Gut, J., Meyer, U.T., Catin, T. and Meyer, U.A. (1986). Mephenytoin type polymorphism in drug oxidation: purification and characterization of a human liver cytochrome P-450 isozyme catalyzing microsomal mephenytoin hydroxylation. Biochem. Biophys. Acta. 884: 435–447.

    Article  CAS  PubMed  Google Scholar 

  • Hall, S.D., Guengerich, F.P., Branch, R.A. and Wilkinson, G.A. (1987). Characterization and inhibition of mephenytoin 4-hydroxylase activity in human liver microsomes. J. Pharmacol. Exp. Ther. 240: 216–222.

    CAS  Google Scholar 

  • Horai, Y., Fujita, K. and Ishizaki, T. (1989). Genetically determined N-acetylation and oxidation capacities in Japanese patients with non occupational urinary bladder cancer. Eur. J. Clin. Pharmacol. 37: 581–587.

    CAS  PubMed  Google Scholar 

  • Hughes, H.B., Schmidt, L.H. and Biehl, J.P. (1955). The metabolism of isoniazid, its implications in therapeutic use. Trans. 14th Conf. Chemother. Tuberc. Washington D.C., U.S. Veterans Adm Army Navy, 217–222.

    Google Scholar 

  • Inaba, T., Jurima, M. and Kalow, W. (1986). Family studies of mephenytoin hydroxylation deficiency. Am. J. Hum. Genet. 38: 768–772.

    CAS  PubMed  Google Scholar 

  • Inaba, T., Jorge, L.F. and Arias, T.D. (1988). Mephenytoin hydroxylation in the Cuna Indians of Panama. Brit. J. Clin. Pharmacol. 25: 75–79.

    CAS  Google Scholar 

  • Iselius, L. and Price Evans, D.A.P. (1983). Formal genetics of isoniazid metabolism in man. Clin. Pharmacokin. 8: 541–544.

    Article  CAS  Google Scholar 

  • Jenne, J.W. (1965). Partial purification and properties of the isoniazid transacetylase in human liver: Its relationship to the acetylation of p-amino-salicylic acid. J. Clin. Invest. 44: 1992–2002.

    Article  CAS  Google Scholar 

  • Kaisary, A., Smith, P., Jaczq, E., McAllister, B., Wilkinson,G.R., Ray, W.A. and Branch, R.A. (1987). Genetic predisposition to bladder cancer: ability to hydroxylate debrisoquine and mephenytoin as risk factors. Can. Res. 47: 5488–5493.

    CAS  Google Scholar 

  • Knodell, R.G., Dubey, R.K., Wilkinson, G.R. and Guengerich, F.P. (1988). Oxidative metabolism in human liver: relationship to polymorphic S-mephenytoin 4-hydroxylation. J. Pharamcol. Exp. Ther. 245: 845–849.

    CAS  Google Scholar 

  • Kroemer, H.K., Mikus, G., Kronbach, T., Meyer, U.A. and Eichelbaum, M. (1989). In vitro characterization of the human cytochrome P-450 involved in polymorphic oxidation of propafenone. Clin. Pharmacol. Ther. 45: 28–33.

    CAS  Google Scholar 

  • Kupfer, A. and Preisig, R. (1984). Pharmacogenetics of mephenytoin: A new drug hydroxylation polymorphism in man. Eur. J. Clin. Pharmacol. 26: 753–759.

    Article  CAS  PubMed  Google Scholar 

  • Kupfer, A. and Branch, R.A. (1985). Stereoselective mephobarbital hydroxylation cosegregates with mephenytoin hydroxylation. Clin. Pharmacol. Ther. 38: 414–418.

    Article  CAS  PubMed  Google Scholar 

  • Kupfer, A., Desmond, P.V., Schenker, S. and Branch, R.A. (1984). Mephenytoin hydroxylation deficiency: kinetics after repeated doses. Clin Pharmacol Ther 35: 33–39.

    CAS  Google Scholar 

  • Mahgoub, A., Idle, J.R., Dring, L.G., Lancaster, R. and Smith, R.L. (1977). Polymorphic hydroxylation of debrisoquine in man. Lancet ii, 584–586.

    Google Scholar 

  • McQueen, E.G. (1980). Pharmacological bases of adverse drug reactions. In Drug Treatment, ed Avery G.S., 2nd edn, pp 202–235 Auckland: Adis Press.

    Google Scholar 

  • Meehan, R.R., Gosden, J.R., Rout, D., Hastie, N.D., Friedberg, T., Adesnik, M., Buckland, R., van Heyningen, V., Fletcher, J., Spurr, N.K., Sweeney, J. and Wolf, C.R. (1988). Human cytochrome P450 PB- 1: a multigene family involved in mephenytoin and steroid oxidation that maps to chromosome 10. Am. J. Hum. Genet. 42: 26–37.

    CAS  PubMed  Google Scholar 

  • Meier, U.T., Dayer, P., Male, P.J., Kronbach, T. and Meyer, U.A. (1985). Mephenytoin hydroxylation polymorphism: characterization of the enzymatic deficiency in liver microsomes of poor metabolizers phenotyped in vivo. Clin. Pharmacol. Ther. 38: 488–494.

    Article  CAS  PubMed  Google Scholar 

  • Meier, U.T. and Meyer, U.A. (1987). Genetic polymorphism of human cytochrome P-450 (S) mephenytoin 4-hydroxylase. Studies with human autoantibodies suggest a functionally altered P-450 isozyme as cause of genetic deficiency. Biochemistry 26: 8466–8474.

    Article  CAS  PubMed  Google Scholar 

  • Meyer, U.A., Skoda, R.C. & Zanger, U.M. (1990). The genetic polymorphism of debrisoquine/sparteine metabolism - molecular mechanisms. Pharmacol Ther,In press.

    Google Scholar 

  • Mitchell, R.S. & Bell, J.C. (1957). Clinical implications of isoniazide PAS and streptomycin blood levels in pulmonary tuberculosis. Trans Am Clin Clim Ass 69: 98–105.

    Google Scholar 

  • Mitchell, J.R., Thorgeirsson, U.P., Black, M., Timbrell, J.A., Snodgrass, W.R., Potter, W.Z., Jollow, D.J. & Keiser, H.R. (1975). Increased incidence of isoniazid hepatitis in rapid acetylators: Possible relation to hydrazine metabolites. Clin Pharmacol Ther 18: 70–79.

    CAS  PubMed  Google Scholar 

  • Musch, E., Eichelbaum, M., Wang, J.K.V., Sassen, W., Castro-Parra, M. ac Dengler, H.J. (1982). Die Häufigkeit hepatotoxischer Nebenwirkungen der tuberkulostatischen Kombinationstherapie (INH, RMP, EMB) in Abhängigkeit vom Acetyliererphänotyp. Klin Wochenschr 60: 513–519.

    Google Scholar 

  • Nakamura, K., Goto, F., Ray W.A., McAllister, C.B., Jacqz, E. Wilkinson, G.R. & Branch, R.A. (1985). Interethnic differences in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin Pharmacol Ther 38: 402–408.

    CAS  Google Scholar 

  • Newton, B.W., Benson, R.C. & McCarriston, C.C. (1966). Sparteine sulphate: A potent capricious oxytocic. Am J Obstet Gynecol 94: 234–241.

    CAS  PubMed  Google Scholar 

  • Platzer, R., Kiipfer, A., Bircher, J. & Preisig, R. (1978). Polymorphic acetylation and aminopyrine demethylation in Gilbert’s syndrome. Eur J Clin Invest 8: 219–223.

    Article  CAS  PubMed  Google Scholar 

  • Price Evans, D.A. (1989). N-Acetyltransferase. Pharmacol Ther 42: 157–234.

    Article  Google Scholar 

  • Price Evans, D.A. & White, T.A. (1964). Human acetylation polymorphism. J Lab Clin Med 63: 394–403.

    Google Scholar 

  • Price Evans, D.A., Manley, K.A. & Mc Kusick, V.A. (1960). Genetic control of isoniazid metabolism in man. Br Med J 2: 485–461.

    Article  Google Scholar 

  • Price Evans,D.A., Mahgoub, A., Sloan, T.P., Idle, J.R. & Smith, R.L. (1980). A family and population study of the genetic polymorphism of debrisoquine oxidation in a white British population. J Med Genet 17: 102–105.

    Google Scholar 

  • Price Evans, D.A., Eze, L.C. & Whibley, E.J. (1983). The association of the slow acetylator phenotype with bladder cancer. J Med Gen 20: 321–329.

    Article  Google Scholar 

  • Price Evans, D.A., Paterson, S., Francisco, P. & Alvarez, G. (1985). The acetylator phenotypes of Saudi Arabian diabetics. J Med Genet 22: 479–483.

    Article  Google Scholar 

  • Raghuram, T.C., Koshakji, R.P., Wilkinson, G.R. & Wood, A.J.J. (1984). Polymorphic ability to metabolize propranolol alters 4-hydroxypropranolol levels but not beta blockade. Clin Pharmacol Ther 36: 51–56.

    Article  CAS  PubMed  Google Scholar 

  • Rao, K.V.N., Mitchison, D.A., Nair, N.G.K., Prema, K. & Tripathy, S.P. (1970). Sulfadimidine acetylation test for classification of patients as slow or rapid inactivators of isoniazide. Br Med J 3: 495–497.

    Article  CAS  PubMed  Google Scholar 

  • Robitzek, E.H., Selikoff, I.J. & Ornstein, G.G. (1952). Chemotherapy of human tuberculosis with hydrazine derivatives of isonicotinic acid. Q Bull Sea View Hosp N.Y. 13: 27–51.

    CAS  Google Scholar 

  • Sanz, E.J., Villen, T., Alm, C. & Bertilsson, L. (1989). S-mephenytoin hydroxylation phenotypes in a Swedish population determined after coadministration with debrisoquine. Clin Pharmacol Ther 45: 495–499.

    Article  CAS  PubMed  Google Scholar 

  • Shah, R.R., Oates, N., Idle, J.R., Smith, R.L. & Lockhart, J.D. (1982). Impaired oxidation of debrisoquine in patients with perhexiline neuropathy. Br Med J 284: 295–299.

    Article  CAS  Google Scholar 

  • Shimada, T., Misono, K.S. & Guengerich, F.P. (1986). Human liver microsomal cytochrome P-450 mephenytoin 4-hydroxylase, a prototype of genetic polymorphism in oxidative drug metabolism: purification and characterization of two similar forms involved in the reaction. J Biol Chem 261: 909–921.

    CAS  PubMed  Google Scholar 

  • Siddoway, L.A., Thompson, K.A., McAllister, C.B., Wang, T., Wilkinson, G.R., Roden, D.M. & Woosley, R.L. (1987). Polymorphism of propafenone metabolism and disposition in man: clinical and pharmacokinetic consequences. Circulation 75: 785–791.

    Article  CAS  PubMed  Google Scholar 

  • Skoda, R., Gonzalez, F.J., Demierre, A. & Meyer, U.A. (1988). Two mutant alleles of the human cytochrome P 450 dbl gene (P 450 IID1) associated with genetically deficient metabolism of debrisoquine and other drugs. Proc Natl Acad Sci 85: 5240–5243.

    CAS  Google Scholar 

  • Sommers, De K., Moncrieff, J. & Avenant, J. (1988). Polymorphism of the 4-hydroxylation of debrisoquine in the San Bushmen of Southern Africa. Human Toxicol 7: 273–276.

    Article  CAS  Google Scholar 

  • Umbenauer, D.R., Martin, M.V., Lloyd, R.S. & Guengerich, F.P. (1987). Cloning and sequence determination of a complementary DNA related to human liver microsomal cytochrome P-450S- mephenytoin 4-hydroxylase. Biochemistry 26: 1094–1099.

    Article  Google Scholar 

  • Ward, S.A., Walle, T., Walle, U.K., Wilkinson, G.R. & Branch, R.A. (1989). Propranolol’s metabolism is determined by both mephenytoin and debrisoquin hydroxylase activities. Clin Pharmacol Ther 45: 72–79.

    Article  CAS  PubMed  Google Scholar 

  • Wedlund, P.J., Aslanian, W.S., McAllister, C.B., Wilkinson, G.R. & Branch, R.A. (1984). Mephenytoin hydroxylation deficiency in Caucasians: frequency of a new oxidative drug metabolism polymorphism. Clin Pharmacol Ther 36: 773–780.

    CAS  Google Scholar 

  • Wedlund, P.J., Aslanian, W.S., Jacgz, E., McAllister, C.B., Branch, R.A. & Wilkinson, G.R. (1985). Phenotypic differences in mephenytoin pharmacokinetics in normal subjects. J Pharmacol Exp Ther 234: 662–669.

    CAS  PubMed  Google Scholar 

  • Wilkinson, G.R., Guengerich, F.P. & Branch, R.A. (1989). Genetic polymorphism of Smephenytoin hydroxylation. Pharmacol Ther 43: 53–76.

    Article  CAS  PubMed  Google Scholar 

  • Woosley, R.L., Drayer, D.E., Reidenberg, M.M., Nies, A.S., Carr, K. & Oates, J.A. (1978). Effect of acetylator phenotype on the rate at which procainamide induces antinuclear antibodies and the lupus syndrome. New Eng1 J Med 298: 1157–1159.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 1991 Plenum Press, New York

About this chapter

Cite this chapter

Gross, A.S., Kroemer, H.K., Eichelbaum, M. (1991). Genetic Polymorphism of Drug Metabolism in Humans. In: Witmer, C.M., Snyder, R.R., Jollow, D.J., Kalf, G.F., Kocsis, J.J., Sipes, I.G. (eds) Biological Reactive Intermediates IV. Advances in Experimental Medicine and Biology, vol 283. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-5877-0_79

Download citation

  • DOI: https://doi.org/10.1007/978-1-4684-5877-0_79

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4684-5879-4

  • Online ISBN: 978-1-4684-5877-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics