Journal of Pharmacokinetics and Biopharmaceutics

, Volume 24, Issue 5, pp 509–519

N-acetyltransferases: Pharmacogenetics and clinical consequences of polymorphic drug metabolism

  • Stephen P. Spielberg
Article

Abstract

Since the discovery of polymorphicN-acetylation of drugs nearly 40 years ago, great progress has been made in understanding the molecular genetics of acetylation as well as the clinical consequences of being a rapid or slow acetylator. Inborn errors (several different alleles) at the NAT2 locus are responsible for the traditional acetylator polymorphism. Studies have revealed variant alleles at the NAT1 locus as well. The consequences of pharmacogenetic variation in these enzymes include (i) altered kinetics of specific drug substrates; (ii) drug-drug interactions resulting from altered kinetics; (iii) idiosyncratic adverse drug reactions. The latter have been extensively investigated for the arylamine-containing sulfonamide antimicrobial drugs. Individual differences in multiple metabolic pathways can increase the likelihood of covalent binding of reactive metabolites of the drugs to cell macromolecules with resultant cytotoxicity and immune response to neoantigens. This can result clinically in an idiosyncratic hypersensitivity reaction, manifested by fever, skin rash, and variable toxicity to organs including liver, bone marrow, kidney, lung, heart, and thyroid. Slow acetylation by NAT2 is a risk factor for such reactions to sulfonamides. Given the incidence of these severe adverse drug reactions (much less than 1/1000), slow acetylation cannot be the sole mechanism of predisposition in the population. Differences in rates of production of hydroxylamine metabolites of the drugs by cytochrome P450 (CYP2C9), myeloperoxidase, and thyroid, roxidase, along with an inherited abnormality in detoxification of the hydroxylamines are critically important in determining individual differences in adverse reaction risk. Both NATs, particularly NAT1, also can further metabolize hydroxylamine metabolites toN-acetoxy derivatives. Intensive investigation of patients with these rare adverse reactions using a variety of tools fromin vitro cell toxicity assays through molecular genetic analysis will help elucidate mechanisms of predisposition and ultimately lead to diagnostic tools to characterize individual risk and prevent idiosyncratic drug toxicity.

Key Words

N-acetyltransferases NAT1 NAT2 sulfonamide hypersensitivity reactions hydroxylamine metabolites 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    W. W. Weber.The Acetylator Genes and Drug Response, Oxford University Press, New York, 1987.Google Scholar
  2. 2.
    D. A. P. Evans.N-acetyltransferases.Pharmacol. Ther. 42:157–234 (1989).PubMedCrossRefGoogle Scholar
  3. 3.
    K. P. Vatsis, W. W. Weber, D. A. Bellet al.. Nomenclature forN-acetyltransferases.Pharmacogenetics 5:1–17 (1995).PubMedCrossRefGoogle Scholar
  4. 4.
    H. B. Hughes. Metabolism of isoniazid in man as related to the occurrence of peripheral neuritis.Am. Rev. Tuberculosis 70:266–273 (1954).Google Scholar
  5. 5.
    D. A. P. Evans, K. A. Manley, and V. A. McKusick. Genetic control of isoniazid metabolism in man.Br. Med. J. 2:485–491 (1960).PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    M. Blum, D. M. Grant, O. W. McBride, M. Heim, and U. A. Meyer. Human arylamineN-acetyltransferase genes: Isolation, chromosomal localization and functional expression.DNA Cell Biol. 9:193–203 (1990).PubMedCrossRefGoogle Scholar
  7. 7.
    T. Deguchi, M. Mashimo, and T. Suzuki. Correlation between acetylator phenotypes and genotypes of polymorphic arylamineN-acetyltransferase in human liver.J. Biol. Chem. 265:12757–12760 (1990).PubMedGoogle Scholar
  8. 8.
    S. Ohsako and T. Deguchi. Cloning and expression of cDNAs for polymorphic and monomorphic arylamineN-acetyltransferases from human liver.J. Biol. Chem. 265:4630–4634 (1990).PubMedGoogle Scholar
  9. 9.
    M. Blum, A. Demierre, D. M. Grant, H. Heim, and U. A. Meyer. Molecular mechanism of slow acetylation of drugs and carcinogens in humans.Proc. Natl. Acad. Sci. U.S. 88:5237–5241 (1991).CrossRefGoogle Scholar
  10. 10.
    D. Hickman and E. Sim.N-acetyltransferase polymorphism: Comparison of phenotype and genotype in humans.Biochem. Pharmacol. 42:1007–1014 (1991).PubMedCrossRefGoogle Scholar
  11. 11.
    K. P. Vatsis, K. J. Martell, and W. W. Weber. Diverse point mutations in the human gene for polymorphicN-acetyltransferase.Proc. Natl. Acad. Sci. U.S. 88:6333–6337 (1991).CrossRefGoogle Scholar
  12. 12.
    D. M. Grant, B. K. Tang, and W. Kalow. A simple test for acetylator phenotype using caffeine.Br. J. Clin. Pharmacol. 17:459–464 (1984).PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    D. Hein, R. Ferguson, M. Dollet al. Molecular genetics of human polymorphicN-acetyltransferase: Enzymatic analysis of 15 recombinant wild-type, mutant, and chimeric NAT2 allozymes.Hum. Mol. Genet. 3:729–734 (1994).PubMedCrossRefGoogle Scholar
  14. 14.
    D. M. Grant, K. Morike, M. Eichelbaum, and U. A. Meyer. Acetylation pharmacogenetics: The slow acetylator phenotype is caused by decreased or absent arylamineN-acetyltransferase in human liver.J. Clin. Invest. 85:968–972 (1990).PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    D. M. Grant, M. Blum, M. Beer, and U. A. Meyer. Monomorphic and polymorphic human arylamineN-acetyltransferases: A comparison of liver isozymes and expressed products of two cloned genes.Mol. Pharmacol. 39:184–191 (1991).PubMedGoogle Scholar
  16. 16.
    D. M. Grant, P. Vohra, Y. Avis, and A. Ima. Detection of a new polymorphism of humanN-acetyltransferase NAT1 usingp-aminosalicyclic acid as anin vivo probe.J. Basic Clin. Physiol. Pharmacol. 3:244 (1992).Google Scholar
  17. 17.
    K. P. Vatsis and W. W. Weber. Structural heterogeneity of caucasianN-acetyltransferase at the NAT1 gene locus.Arch. Biochem. Biophys. 310:71–76 (1993).CrossRefGoogle Scholar
  18. 18.
    N. Hughes and D. M. Grant. Cloning and expression of new mutant forms of humanN-acetyltransferase NAT1 with defective function.10th International Symposium on Microsomes and Drug Oxidations, Toronto, 1994, p. 278.Google Scholar
  19. 19.
    B. L. Lee, D. Wong, N. L. Benowitz, and P. M. Sullam. Altered patterns of drug metabolism in patients with the acquired immunodeficiency syndrome.Clin. Pharmacol. Ther. 53:529–535 (1993).PubMedCrossRefGoogle Scholar
  20. 20.
    D. M. Grant, P. D. Josephy, H. L. Lord, and L. D. Morrison.Salmonella typhimurium strains expressing human arylamineN-acetyltransferases: Metabolic and mutagenic activation of aromatic amines.Cancer Res. 52:3961–3964 (1992).PubMedGoogle Scholar
  21. 21.
    D. E. Drayer and M. M. Reidenberg. Clinical consequences of polymorphic acetylation of drugs.Clin. Pharmacol. Ther. 22:251–258 (1977).PubMedGoogle Scholar
  22. 22.
    N. H. Shear, S. P. Spielberg, D. M. Grant, B. K. Tang, and W. Kalow. Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity.Ann. Intern. Med. 105:179–184 (1986).PubMedCrossRefGoogle Scholar
  23. 23.
    M. J. Rieder, N. H. Shear, A. Kanee, B. K. Tang, W. Kalow, and S. P. Spielberg. Predominance of slow acetylator phenotype among patients with sulfonamide hypersensitivity reactions.Clin. Pharmacol. Ther. 49:13–17 (1991).PubMedCrossRefGoogle Scholar
  24. 24.
    N. H. Shear and S. P. Spielberg.In vitro evaluation of a toxic metabolite of sulfadiazine.Can. J. Physiol. Pharmacol. 63:1370–1372 (1985).PubMedCrossRefGoogle Scholar
  25. 25.
    A. E. Cribb and S. P. Spielberg. Hepatic microsomal metabolism of sulfamethoxazole to the hydroxylamine.Drug. Metab. Disp. 18:784–787 (1990).Google Scholar
  26. 26.
    A. E. Cribb, M. Miller, A. Tesoro, and S. P. Spielberg. Peroxidase-dependent oxidation of sulfonamides by monocytes and neutrophils from man and dog.Mol. Pharmacol. 38:744–751 (1990).PubMedGoogle Scholar
  27. 27.
    A. Gupta, M. M. Eggo, J. P. Uetrechtet al. Drug-induced hypothyroidism: The thyroid as a target organ in hypersensitivity reactions to anticonvulsants and sulfonamides.Clin. Pharmacol. Ther. 51:56–67 (1992).PubMedCrossRefGoogle Scholar
  28. 28.
    A. E. Cribb and S. P. Spielberg. Sulfamethoxazole is metabolized to the hydroxylamine in humans.Clin. Pharmacol. Ther. 51:522–526 (1992).PubMedCrossRefGoogle Scholar
  29. 29.
    A. E. Cribb, S. P. Spielberg, and G. P. Griffin.N4-Hydroxylation of sulfamethoxazole by cytochrome P450 of the CYP2C subfamily, and reduction of sulfamethoxazole in human and rat hepatic microsomes.Drug Metab. Disp. 23:406–414 (1995).Google Scholar
  30. 30.
    M. J. Rieder, J. P. Uetrecht, and S. P. Spielberg. Synthesis and toxicity of hydroxylamines of the sulfonamides.J. Pharmacol. Exp. Ther. 244:724–728 (1988).PubMedGoogle Scholar
  31. 31.
    M. J. Rieder, J. P. Uetrecht, N. H. Shear, M. Cannon, M. Miller, and S. P. Spielberg. Diagnosis of sulfonamide hypersensitivity reactions byin vitro “re-challenge” with hydroxylamine metabolites.Ann. Intern. Med. 110:286–289 (1989).PubMedCrossRefGoogle Scholar
  32. 32.
    U. Giger, L. L. Werner, N. J. Millichamp, and N. T. Gorman. Sulfadiazine-induced allergy in six Doberman Pinschers.J. Am. Vet. Med. Assoc. 186:479–484 (1985).PubMedGoogle Scholar
  33. 33.
    A. E. Cribb and S. P. Spielberg. Anin vitro investigation of predisposition to sulfonamide idiosyncratic toxicity in dogs.Vet. Res. Commun. 14:241–252 (1990).PubMedCrossRefGoogle Scholar
  34. 34.
    A. E. Cribb, M. A. Miller, J. S. Leeder, and S. P. Spielberg. Reactions of the nitroso and hydroxylamine metabolites of sulfamethoxazole with reduced glutathione: Implications for idiosyncratic toxicity.Drug Metab. Disp. 19:900–906 (1991).Google Scholar
  35. 35.
    R. Riley, A. E. Cribb, and S. P. Spielberg. Glutathione-S-transferase mu is not a marker for sulfonamide hypersensitivity reactions.Biochem. Pharmacol. 42:696–698 (1991).PubMedCrossRefGoogle Scholar
  36. 36.
    R. Buhl, H. A. Jaffe, K. J. Holroyd,et al. Systemic glutathione deficiency in symptomfree HIV seropositive individuals.Lancet 2:1294–1298 (1989).PubMedCrossRefGoogle Scholar
  37. 37.
    F. M. Gordon, G. L. Simon, C. B. Wofsy, and J. Mills. Adverse reactions to trimethoprim-sulfamethoxazole in patients with the acquired immunodeficiency syndrome.Ann. Intern. Med. 100:495–499 (1984).CrossRefGoogle Scholar
  38. 38.
    I. Medina, J. Mills, G. Leounget al. Oral therapy for pneunocystis carinii pneumonia in the acquired immunodeficiency syndrome. A controlled trial of trimethoprim-sulfa-methoxazole vs. trimethoprim-dapsone.New Engl. J. Med. 323:776–782 (1990).PubMedCrossRefGoogle Scholar
  39. 39.
    H. Nakamura, J. Uetrecht, D. M. Grant, and S. P. Spielberg. Metabolism and toxicity ofN-acetoxy-sulfamethoxazole.J. Pharmacol. Exp. Ther. 274:1099–1104 (1995).PubMedGoogle Scholar
  40. 40.
    A. E. Cribb, D. M. Grant, and S. P. Spielberg. Expression of the monomorphic arylamineN-acetyltransferase (NAT1) in human leukocytes.J. Pharmacol. Exp. Ther. 259:1241–1246 (1991).PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1996

Authors and Affiliations

  • Stephen P. Spielberg
    • 1
  1. 1.Merck Research LaboratoriesBlue Bell

Personalised recommendations