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.
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References
W. W. Weber.The Acetylator Genes and Drug Response, Oxford University Press, New York, 1987.
D. A. P. Evans.N-acetyltransferases.Pharmacol. Ther. 42:157–234 (1989).
K. P. Vatsis, W. W. Weber, D. A. Bellet al.. Nomenclature forN-acetyltransferases.Pharmacogenetics 5:1–17 (1995).
H. B. Hughes. Metabolism of isoniazid in man as related to the occurrence of peripheral neuritis.Am. Rev. Tuberculosis 70:266–273 (1954).
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).
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).
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).
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).
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).
D. Hickman and E. Sim.N-acetyltransferase polymorphism: Comparison of phenotype and genotype in humans.Biochem. Pharmacol. 42:1007–1014 (1991).
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).
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).
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).
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).
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).
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).
K. P. Vatsis and W. W. Weber. Structural heterogeneity of caucasianN-acetyltransferase at the NAT1 gene locus.Arch. Biochem. Biophys. 310:71–76 (1993).
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.
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).
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).
D. E. Drayer and M. M. Reidenberg. Clinical consequences of polymorphic acetylation of drugs.Clin. Pharmacol. Ther. 22:251–258 (1977).
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).
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).
N. H. Shear and S. P. Spielberg.In vitro evaluation of a toxic metabolite of sulfadiazine.Can. J. Physiol. Pharmacol. 63:1370–1372 (1985).
A. E. Cribb and S. P. Spielberg. Hepatic microsomal metabolism of sulfamethoxazole to the hydroxylamine.Drug. Metab. Disp. 18:784–787 (1990).
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).
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).
A. E. Cribb and S. P. Spielberg. Sulfamethoxazole is metabolized to the hydroxylamine in humans.Clin. Pharmacol. Ther. 51:522–526 (1992).
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).
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).
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).
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).
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).
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).
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).
R. Buhl, H. A. Jaffe, K. J. Holroyd,et al. Systemic glutathione deficiency in symptomfree HIV seropositive individuals.Lancet 2:1294–1298 (1989).
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).
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).
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).
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).
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Spielberg, S.P. N-acetyltransferases: Pharmacogenetics and clinical consequences of polymorphic drug metabolism. Journal of Pharmacokinetics and Biopharmaceutics 24, 509–519 (1996). https://doi.org/10.1007/BF02353477
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DOI: https://doi.org/10.1007/BF02353477