Functional characterization of human N-acetyltransferase 2 (NAT2) single nucleotide polymorphisms.

N-Acetyltransferase 2 (NAT2) catalyses the activation and/or deactivation of a variety of aromatic amine drugs and carcinogens. Polymorphisms in the N-acetyltransferase 2 (NAT2) gene have been associated with a variety of drug-induced toxicities, as well as cancer in various tissues. Eleven single nucleotide polymorphisms (SNPs) have been identified in the NAT2 coding region, but the specific effects of each of these SNPs on expression of NAT2 protein and N-acetyltransferase enzymatic activity are poorly understood.

DNA adduct levels and absence of tumors in female rapid and slow acetylator congenic hamsters administered the rat mammary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine.

N-acetyltransferases (EC 2.3.1.

Oral administration of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) yields PhIP-DNA adducts but not tumors in male Syrian hamsters congenic at the N-acetyltransferase 2 (NAT2) locus.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic amine carcinogen present in well-done meat. PhIP must undergo host-mediated bioactivation to exert its mutagenic and carcinogenic effects. Following N-hydroxylation, N-acetyltransferases catalyze the O-acetylation (activation) of N-hydroxy-PhIP to an electrophile causing DNA damage.

Pharmacogenetics of the arylamine N-acetyltransferases: a symposium in honor of Wendell W. Weber.

This article is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics presented at the joint meeting of the American Society for Biochemistry and Molecular Biology and the American Society for Pharmacology and Experimental Therapeutics, June 4-8, Boston, Massachusetts. The presentations focused on the pharmacogenetics of the NAT1 and NAT2 arylamine N-acetyltransferases, including developmental regulation, structure-function relationships, and their possible role in susceptibility to breast, colon, and pancreatic cancers. The symposium honored Wendell W.

N-Acetyltransferase-2 genetic polymorphism, well-done meat intake, and breast cancer risk among postmenopausal women.

Heterocyclic amines found in well-done meat require host-mediated metabolic activation before initiating DNA mutations and tumors in target organs. Polymorphic N-acetyltransferase-2 (NAT2) catalyzes the activation of heterocyclic amines via O-acetylation, suggesting that NAT2 genotypes with high O-acetyltransferase activity (rapid/intermediate acetylator phenotype) increase the risk of breast cancer in women who consume well-done meat. To test this hypothesis, DNA samples and information on diet and other breast cancer risk factors were obtained from a nested case-control study of postmenopausal women.

DNA adduct levels and intestinal lesions in congenic rapid and slow acetylator syrian hamsters admi food mutagens 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) or 2-amino-3-methylimidazo[4,5-f]quinoline (IQ).

Epidemiological studies indicate that rapid acetylators with a high intake of well-done red meat have an increased risk of colorectal cancer. Arylamine N-acetyltransferase enzymes (E.C.

A role for bioactivation and covalent binding within epidermal keratinocytes in sulfonamide-induced cutaneous drug reactions.

Cutaneous reactions are the most common manifestation of delayed-type hypersensitivity caused by sulfamethoxazole and dapsone. In light of the recognized metabolic and immunologic activity of the skin, we investigated the potential role of normal human epidermal keratinocytes in the development of these reactions. Adult and neonatal normal human epidermal keratinocytes metabolized sulfamethoxazole and dapsone to N-4-hydroxylamine and N-acetyl derivatives in a time-dependent manner.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine induces a higher number of aberrant crypt foci in Fischer 344 (rapid) than in Wistar Kyoto (slow) acetylator inbred rats.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant heterocyclic amine carcinogen in the human diet and is a colon carcinogen in the rat. N-Acetyltransferase-2 (NAT2) catalyzes the conversion of PhIP and other heterocyclic amines to a DNA-reactive form. NAT2 has a polymorphic distribution in humans and other mammals, including rats.

Acetylator phenotype and genotype in patients infected with HIV: discordance between methods for phenotype determination and genotype.

The acetylator phenotype and genotype of AIDS patients, with and without an acute illness, was compared with that of healthy control subjects (30 per group). Two probe drugs, caffeine and dapsone, were used to determine the phenotype in the acutely ill cohort. Polymerase chain reaction amplification and restriction fragment length polymorphism analysis served to distinguish between the 26 known NAT2 alleles and the 21 most common NAT1 alleles.

Association between acetylator genotype and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) DNA adduct formation in colon and prostate of inbred Fischer 344 and Wistar Kyoto rats.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a heterocyclic amine (HCA) found in cooked meats, causes colon and prostate tumors in male rats. Polymorphic N-acetyltransferase metabolizes N-hydroxy-PhIP to a DNA-reactive form. Liver, colon, and prostate PhIP-DNA adduct levels were compared in male rapid-acetylator Fischer 344 (F344) and slow-acetylator Wistar-Kyoto (WKY) rats fed 0.

N-Acetyltransferase genetics and their role in predisposition to aromatic and heterocyclic amine-induced carcinogenesis.

N-Acetyltransferases (EC 2.3.1.

Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms.

The focus of this review is the molecular genetics, including consensus NAT1 and NAT2 nomenclature, and cancer epidemiology of the NAT1 and NAT2 acetylation polymorphisms. Two N-acetyltransferase isozymes, NAT1 and NAT2, are polymorphic and catalyze both N-acetylation (usually deactivation) and O-acetylation (usually activation) of aromatic and heterocyclic amine carcinogens. Epidemiological studies suggest that the NAT1 and NAT2 acetylation polymorphisms modify risk of developing urinary bladder, colorectal, breast, head and neck, lung, and possibly prostate cancers.

Laryngocele: an anatomical variant.

It is commonly believed that external laryngoceles always penetrate the thyrohyoid membrane at the site of penetration of the neurovascular bundle. We present a case where the site of penetration was posterosuperior to this. Careful dissection of the neck of a laryngocele sac is important to prevent damage to the neurovascular bundle.

Novel human N-acetyltransferase 2 alleles that differ in mechanism for slow acetylator phenotype.

Three novel human NAT2 alleles (NAT2*5D, NAT2*6D, and NAT2*14G) were identified and characterized in a yeast expression system. The common rapid (NAT2*4) and slow (NAT2*5B) acetylator human NAT2 alleles were also characterized for comparison. The novel recombinant NAT2 allozymes catalyzed both N- and O-acetyltransferase activities at levels comparable with NAT2 5B and significantly below NAT2 4, suggesting that they confer slow acetylation phenotype.

Prostate-specific human N-acetyltransferase 2 (NAT2) expression in the mouse.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic amine identified in the human diet and in cigarette smoke that produces prostate tumors in the rat. PhIP is bioactivated by cytochrome P-450 enzymes to N-hydroxylated metabolites that undergo further activation by conjugation enzymes, including the N-acetyltransferases, NAT1 and NAT2. To investigate the role of prostate-specific expression of human N-acetyltransferase 2 (NAT2) on PhIP-induced prostate cancer, we constructed a transgenic mouse model that targeted expression of human NAT2 to the prostate.

Dietary selenium reduces the formation of aberrant crypts in rats administered 3,2'-dimethyl-4-aminobiphenyl.

Human epidemiologic studies suggest that low selenium status is associated with increased cancer risk and that selenium supplementation is associated with reduction in the incidence of several cancers, including colorectal cancer. Aromatic and heterocyclic amine carcinogens are thought to be important in the etiology of human colorectal cancer, but no information is available on the effects of selenium on aromatic amine-induced colon cancer. In order to investigate this effect, aberrant crypt foci (ACF), the putative preneoplastic lesions of colon cancer in humans and rodents, were used as a biomarker to test the hypothesis that selenium supplementation can reduce aromatic amine-induced colon carcinogenesis.

Higher DNA adduct levels in urinary bladder and prostate of slow acetylator inbred rats administered 3,2'-dimethyl-4-aminobiphenyl.

Human epidemiological studies suggest associations between acetylator phenotype and aromatic amine-induced tumors. The aromatic amine carcinogen 3,2'-dimethyl-4-aminobiphenyl (DMABP) induces colon, prostate, and urinary bladder tumors in the rat, and a rapid and slow acetylator rat model has been characterized. The formation of DNA adducts has been used as a valuable biomarker in tumorigenesis.

Symposium overview: the role of genetic polymorphism and repair deficiencies in environmental disease.

A symposium of this title was presented at the 37th Annual Meeting of the Society of Toxicology held in Seattle, Washington during March of 1998. The symposium focused on heritable variations in metabolism, DNA replication, and DNA repair that may predispose humans to environmental diseases. Human metabolic, replication, and repair enzymes function in protective roles.

N-acetyltransferase 1 genetic polymorphism, cigarette smoking, well-done meat intake, and breast cancer risk.

N-Acetyltransferase 1 (NAT1), encoded by the polymorphic NAT1 gene, has been shown to be one of the major enzymes in human breast tissue that activates aromatic and heterocyclic amines. Humans are mainly exposed to these carcinogens through cigarette smoking and consumption of well-done meat. To test the hypothesis that variations in the NAT1 gene are related to breast cancer risk, particularly among women who smoke or consume high levels of well-done meat, a nested case-control study was conducted in a prospective cohort study of 41,837 postmenopausal Iowa women.

The chemical form of selenium influences 3,2'-dimethyl-4-aminobiphenyl-DNA adduct formation in rat colon.

There is increasing evidence that selenium can protect against tumorigenesis or preneoplastic lesion development induced by chemical carcinogens. This study examined whether selenite, selenate or selenomethionine would be protective against 3, 2'-dimethyl-4-aminobiphenyl (DMABP)-DNA adduct formation in the liver and colon of rats and sought to delineate the mechanism for the protective effects of the different chemical forms of selenium against aberrant crypt formation, a preneoplastic lesion for colon cancer. After injection of DMABP, two DNA adducts were identified in the liver and colon of rats.

A restriction fragment length polymorphism assay that differentiates human N-acetyltransferase-1 (NAT1) alleles.

Currently there is much interest in the N-acetyltransferase-1 (NAT1) genetic polymorphism and its relationship to cancer. Previous studies have described methods to distinguish NAT1 alleles through polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) and/or allele-specific amplification. However, these methods detect at most only four of the NAT1 alleles identified in human populations.