Monomorphic and polymorphic human arylamine N-acetyltransferases: a comparison of liver isozymes and expressed products of two cloned genes

A genetic polymorphism of human liver arylamine N-acetyltransferase (NAT; EC 2.3.1.5) enzyme activity divides populations into distinguishable "slow acetylator" and "rapid acetylator" phenotypes. Two human genes, NAT1 and NAT2, encoding NAT proteins [DNA Cell Biol. 9:193-203 (1990)] were transiently expressed in cultured monkey kidney COS-1 cells, and the resulting recombinant NAT1 and NAT2 proteins were compared with N-acetyltransferase activities in human liver cytosol with respect to their stability, chromatographic behavior on anion exchange columns, electrophoretic mobility, and arylamine acceptor substrate specificity. NAT1 was far less stable in vitro than NAT2. Under conditions designed to optimize enzyme stability, anion exchange chromatography experiments revealed that enzymes corresponding to both recombinant NAT1 and NAT2 were expressed in human liver. Recombinant and human liver NAT1 enzymes showed the same characteristic selectivity (low apparent Km, high Vmax) for the "monomorphic" substrates p-aminosalicylic acid and p-aminobenzoic acid. Such substrates fail to discriminate between the acetylator phenotypes in vivo. The same criteria established that recombinant NAT2 was indistinguishable from one of two previously observed N-acetyltransferases (NAT2A and NAT2B) whose liver contents correlate with acetylator phenotype in human populations. Recombinant NAT2 and the liver NAT2 isoforms NAT2A and NAT2B selectivity N-acetylated the "polymorphic" substrates sulfamethazine and procainamide, whose disposition in vivo is affected by the acetylation polymorphism. Interestingly, the carcinogen 2-aminofluorene was very efficiently metabolized by both NAT1 and NAT2. Independent regulation of NAT1 and NAT2 genes was suggested by a lack of correlation of NAT1 and NAT2 enzyme activities in cytosols from 39 human livers. The results provide strong evidence that the NAT2 locus is the site of the human acetylation polymorphism. In addition, the use of recombinant NAT1 and NAT2 will allow us to predict whether any given arylamine will be polymorphically acetylated in humans.     

Arylamine N-Acetyltransferase in Erythrocytes of Cystic Fibrosis Patients

Abstract: Sulphamethoxazole, a substrate of human arylamine N-acetyltransferase, is used in the treatment of cystic fibrosis patients, who metabolise the drug rapidly. Increased metabolic clearance of sulphamethoxazole has been suggested to account for this rapid metabolism. Arylamine N-acetyltransferase type 1 is expressed in erythrocytes and leucocytes and the activity in erythrocytes is shown to contribute approximately 99% of the activity of arylamine N-acetyltransferase type 1 in blood cells. Arylamine N-acetyltransferase type 1 activity in erythrocytes from 16 adult cystic fibrosis patients and 19 age-matched controls were compared. Although there is a variation in erythrocyte arylamine N-acetyltransferase type 1 activity within each group, no difference was found when the two groups were compared. All individuals from the cystic fibrosis and control groups were investigated for certain allelic variants of the arylamine N-acetyltransferase type 1 gene (NAT1). Only one copy of a mutant NAT1 allele (NATI*11) was found. The heterozygous NAT1 individual is a cystic fibrosis patient with a low level of erythrocyte arylamine N-acetyltransferase type 1 activity. A second distinct arylamine N-acetyltransferase isozyme, arylamine N-acetyltransferase type 2, is encoded at the multi-allelic NAT2 locus. There was no correlation between erythrocyte arylamine N-acetyltransferase-1 activity and NAT2 alleles present in either the cystic fibrosis or control groups. The distribution of NA T2 alleles was very similar in the two groups. The increased clearance of sulphamethoxazole in cystic fibrosis patients appears unlikely to be due to erythrocyte arylamine N-acetyltransferase type 1 activity or to inheritance of alleles at either the NA T1 or NA T2 loci.     

Phenotype of the most common "slow acetylator" arylamine N-acetyltransferase 1 genetic variant (NAT1*14B) is substrate-dependent

Human arylamine N-acetyltransferase 1 (NAT1) is a phase II cytosolic enzyme responsible for the activation or deactivation of many arylamine compounds including pharmaceuticals and environmental carcinogens. NAT1 is highly polymorphic and has been associated with altered risk toward many cancers. NAT1*14B is characterized by a single nucleotide polymorphism in the coding region (rs4986782; 560G>A; R187Q). NAT1*14B is associated with higher frequency of smoking-induced lung cancer and is the most common "slow acetylator" arylamine NAT1 genetic variant. Previous studies have reported decreased N- and O-acetylation capacity and increased proteasomal degradation of NAT1 14B compared with the referent, NAT1 4. The current study is the first to investigate NAT1*14B expression using constructs that completely mimic NAT1 mRNA by including the 5'- and 3'-untranslated regions, together with the open reading frame of the referent, NAT1*4, or variant, NAT1*14B. Our results show that NAT1 14B is not simply associated with "slow acetylation." NAT1 14B-catalyzed acetylation phenotype is substrate-dependent, and NAT1 14B exhibits higher N- and O-acetylation catalytic efficiency as well as DNA adducts after exposure to the human carcinogen 4-aminobiphenyl.     

Genotyping human polymorphic arylamine N-acetyltransferase: identification of new slow allotypic variants.

Arylamine N-acetyltransferase catalyses the N-acetylation of primary arylamine and hydrazine drugs and chemicals. N-acetylation is subject to a polymorphism and humans can be categorized as either fast or slow acetylators according to their ability to N-acetylate polymorphic substrates in vivo. Previously, slow acetylation has been linked to four distinct polymorphic N-acetyltransferase (pnat) alleles each of which contains one or more point mutations within the coding region of the pnat gene. One new rare slow variant of pnat has been identified by cloning and sequencing the pnat DNA from an individual whose NAT phenotype was determined by in vivo acetylation of the polymorphic substrate sulphamethazine. This allele, designated S1c, differs from the wild type fast allele at nucleotide positions 341 and 803. A second new rare slow allotypic variant, designated S3, has been identified by resistance of the pnat specific DNA to digestion with the restriction enzymes Fok I and Bam HI. A method of genotyping individuals for the arylamine N-acetyltransferase (NAT) polymorphism is presented which correctly predicts the phenotype of greater than 95% (21 of 22) of individuals as measured by the extent of acetylation of sulphamethazine in urine. This refined genotyping method was applied to a clinical population of 48 Caucasians with classical or definite rheumatoid arthritis each receiving daily between 150 and 500 mg of the anti-rheumatic drug, D-penicillamine. There is no difference in the N-acetyltransferase phenotype of the individuals who developed proteinuria and the control group with no adverse effects.     

Paclitaxel (taxol) inhibits the arylamine N-acetyltransferase activity and gene expression (mRNA NAT1) and 2-aminofluorene-DNA adduct formation in human bladder carcinoma cells (T24 and TSGH 8301)

Acetylator polymorphism in man results from differential expression of human liver N-acetyltransferase. N-Acetyltransferase enzyme activity has been demonstrated to be involved in some types of chemical carcinogenesis. Paclitaxel (taxol) had been shown to affect N-acetyltransferase activity of human lung cancer cells. In this study, paclitaxel was chosen to investigate the effects of arylamine N-acetyltransferase activity (N-acetylation of substrate), gene expression and 2-aminofluorene-DNA adduct formation in human bladder carcinoma cell lines (T24 and TSGH 8301). The N-acetyltransferase activity (N-acetylation of substrates) was determined by high performance liquid chromatography assaying for the amounts of acetylated 2-aminofluorene and p-aminobenzoic acid and nonacetylated 2-aminofluorene and p-aminobenzoic acid. Intact human bladder carcinoma T24 and TSGH 8301 cells were used for examining N-acetyltransferase activity, gene expression and 2-aminofluorene-DNA adduct formation. The results demonstrated that the N-acetyltransferase activity, gene expression (NAT1 mRNA) and 2-aminofluorene-DNA adduct formation in intact human bladder carcinoma cells were inhibited and decreased by paclitaxel in a dose-dependent manner. The effects of paclitaxel on the apparent values of Km and Vmax of N-acetyltransferase enzyme from intact human bladder carcinoma cells were also determined in these cell lines. A marked influence of paclitaxel was observed on the decreasing apparent values of Km and Vmax from intact human bladder carcinoma cells (T24 and TSGH 8301). Thus, paclitaxel is an uncompetitive inhibitor to the NAT enzyme.     

Purification and biochemical characterization of hepatic arylamine N-acetyltransferase from rapid and slow acetylator mice: identity with arylhydroxamic acid N,O-acyltransferase and N-hydroxyarylamine O-acetyltransferase

An inbred mouse model for the human N-acetylation polymorphism has been used to investigate the biochemical basis for the arylamine N-acetylation polymorphism and the relationship between the cytosolic enzymes arylamine N-acetyltransferase (NAT), arylhydroxamic acid N,O-acyltransferase, and N-hydroxyarylamine O-acetyltransferase. Biochemical studies of partially purified NAT from rapid and slow acetylator mice revealed identical molecular weights of 31,500, activation energies of 21,000 cal/mol, equivalent affinities for acetyl coenzyme A, broad pH optima, the presence of an active site sulfhydryl group, and similar behavior during purification with anion exchange, gel filtration, and hydrophobic interaction chromatography. The enzymes differed in inhibition by hydrogen peroxide and dithiobis(2-nitrobenzoic acid). These observations taken in conjunction with previous investigations indicate that the rapid and slow mouse NAT enzymes are isozymes with minimal structural differences. NATs from rapid and slow acetylator mice were purified more than 10,000-fold by the following sequence of methods: homogenization and fractional centrifugation, protamine sulfate precipitation, and chromatography on DEAE-Trisacryl M, Sephadex G-100, Amethopterin-AH-Sepharose 4B, butyl agarose, and Sephacryl S-200, with a 15-25% recovery. NAT from B6 mice was purified to greater than 95% purity, as judged by silver staining of sodium dodecyl sulfate-polyacrylamide gels. Although only NAT appeared to be subject to a genetic polymorphism as evidenced by N-acetylation activities in liver cytosol, the purified NAT protein possessed arylhydroxamic acid N,O-acyltransferase, N-hydroxyarylamine O-acetyltransferase, and NAT activities. Thus, the cytosolic N-acetyltransferase of mouse liver may catalyze N-, O-, and N,O-acetyltransfer reactions through a common acetylated intermediate of a single protein.     

N-acetyltransferase is involved in baicalein-induced N-acetylation of 2-aminofluorene and DNA-2-aminofluorene adduct formation in human leukemia HL-60 cells

Many arylamine and hydrazine drugs are acetylated by cytosolic N-acetyltransferase (NAT). The human promyelocytic leukemia cell line (HL-60) has been shown to acetylate arylamine and contain NAT activity. The purpose of this study was to determine whether or not baicalein could affect N-acetylation of 2-aminofluorene (AF) in HL-60 cells. Acetylated and nonacetylated AF were determined by using high performance liquid chromatography. Baicalein displayed a dose-dependent inhibition of cytosolic and intact cells' NAT activity and reduced the number of viable cells. Time-course experiments showed that N-acetylation of AF, measured from intact HL-60 cells, was inhibited by baicalein for up to 48 h. Baicalein also decreased AF-DNA adduct formation in the examined cells. The effects of baicalein on NAT were examined by flow cytometry and NAT gene expression was examined by polymerase chain reaction. The results demonstrated that baicalein inhibited NAT1 mRNA gene expression and reduced the level of NAT in HL-60 cells. These results show that baicalein can affect the NAT activity of human leukemia cells in vitro.     

Human acetylator genotype: Relationship to colorectal cancer incidence and arylamine N-acetyltransferase expression in colon cytosol

Polymorphic expression of arylamine N-acetyltransferase (EC 2.3.1.5) may be a differential risk factor in metabolic activation of arylamine carcinogens and susceptibility to cancers related to arylamine exposures. Human epidemiological studies suggest that rapid acetylator phenotype may be associated with higher incidences of colorectal cancer. We used restriction fragment length polymorphism analysis to determine acetylator genotypes of 44 subjects with colorectal cancer and 28 non-cancer subjects of similar ethnic background (i.e., approximately 25% Black and 75% White). The polymorphic N-acetyltransferase gene (NAT2) was amplified by the polymerase chain reaction from DNA templates derived from human colons of colorectal and non-cancer subjects. No significant differences inNAT2 allelic frequencies (i.e., WT, M1, M2, M3 alleles) or in acetylator genotypes were found between the colorectal cancer and non-cancer groups. No significant differences inNAT2 allelic frequencies were observed between Whites and Blacks or between males and females. Cytosolic preparations from the human colons were tested for expression of arylamine N-acetyltransferase activity. Although N-acetyltransferase activity was expressed for each of the arylamines tested (i.e., p-aminobenzoic acid, 4-aminobiphenyl, 2-aminofluorene, -naphthylamine), no correlation was observed between acetylator genotype and expression of human colon arylamine N-acetyltransferase activity. Similarly, no correlation was observed between subject age and expression of human colon arylamine N-acetyltransferase activity. These results suggest that arylamine N-acetyltransferase activity expressed in human colon is catalyzed predominantly by NAT1, an arylamine N-acetyltransferase that is not regulated byNAT2 acetylator genotype. The ability to determine acetylator genotype from DNA derived from human surgical samples should facilitate further epidemiological studies to assess the role of acetylator genotype in various cancers.     

Localization of N-acetyltransferases NAT1 and NAT2 in human tissues.

Human acetyl coenzyme A-dependent N-acetyltransferase (EC 2.3.1.5) (NAT) catalyzes the biotransformation of a number of arylamine and hydrazine compounds. NAT isozymes are encoded at 2 loci; one encodes NAT1, formerly known as the monomorphic form of the enzyme, while the other encodes the polymorphic NAT2, which is responsible for individual differences in the ability to acetylate certain compounds. Human epidemiological studies have suggested an association between the "acetylator phenotype" and particular cancers such as those of the bladder and colon. In the present study, NAT1- and NAT2-specific riboprobes were used in hybridization histochemistry studies to localize NAT1 and NAT2 mRNA sequences in formalin-fixed, paraffin-embedded human tissue sections. Expression of both NAT1 and NAT2 mRNA was observed in liver, gastrointestinal tract tissues (esophagus, stomach, small intestine, and colon), ureter, bladder, and lung. In extrahepatic tissues, NAT1 and NAT2 mRNA expression was localized to intestinal epithelial cells, urothelial cells, and the epithelial cells of the respiratory bronchioles. The observed heterogeneity of NAT1 and NAT2 mRNA expression between human tissue types may be of significance in assessing their contribution to known organ-specific toxicities of various arylamine drugs and carcinogens.     

Ellagic acid inhibits growth and arylamine N-acetyltransferase activity and gene expression in Staphylococcus aureus

It is well documented that N-acetyltransferase (NAT) plays a key role in the N-acetylation of arylamine compounds. Ellagic acid was demonstrated to elicit dose-dependent bacteriostatic activity and inhibition of N-acetylation of 2-aminofluorene (AF). N-acetylation of AF in S. aureus was determined by high preformance liquid chromatography. The apparent values of Km and Vmax of NAT were decreased after co-treatment with 0.5 mM ellagic acid in the cytosol of S. aureus. PCR also indicated that ellagic acid inhibited NAT gene expression (NAT mRNA) in S. aureus.     

The effect of paclitaxel on 2-aminofluorene-DNA adducts formation and arylamine N-acetyltransferase activity and gene expression in human lung tumor cells (A549).

In this study, paclitaxel was used to determine inhibition of arylamine N-acetyltransferase (NAT) activity, gene expression and 2-aminofluorene-DNA adduct formation in a human lung tumor cell line (A549). The activity of NAT was measured by HPLC assaying for the amounts of N-acetyl-2-aminofluorene (2-AAF) and remaining 2-aminofluorene (2-AF). Human lung tumor cell cytosols and intact cells were used for examining NAT activity and carcinogen-DNA adduct formation. The results demonstrated that NAT activity, gene expression (NAT1 mRNA) and 2-AF-DNA adduct formation in human lung tumor cells were inhibited and decreased by paclitaxel in a dose-dependent manner. The effects of paclitaxel on the values of the apparent Km and Vmax of NAT from human lung tumor cells were also determined in both examined systems. The result also indicated that paclitaxel decreased the apparent values of Km and Vmax from human lung tumor cells in both cytosol and intact cells. Thus, paclitaxel is an uncompetitive inhibitor to NAT enzyme.     

Pharmacogenetics of the human arylamine N-acetyltransferases

This review briefly describes current understanding of one of the earliest discovered pharmacogenetic polymorphisms of drug biotransformation affecting acetylation of certain homo- and heterocyclic aromatic amines and hydrazines. This so-called acetylation polymorphism arises from allelic variation in one of the two known human arylamine N-acetyltransferase genes, namely NAT2, which results in production of NAT2 proteins with variable enzyme activity or stability. The NAT1 gene locus encodes a structurally related enzyme, NAT1, with catalytic specificity for arylamine acceptor substrates distinct from that exhibited by NAT2. NAT1 function is also genetically variable in human populations. Clinical and toxicological consequences of genetic variation in NAT1 and NAT2 activity are discussed.     

Arylamine N-acetyltransferase in human red blood cells.

N-Acetyltransferase activities associated with erythrocytes from 20 individuals have been determined with p-aminobenzoic acid as substrate. A three-fold variation in Vmax is found. The N-acetyltransferase genotype of the individuals has been determined and there is no correlation between the extent of acetylation measured in the individuals' erythrocytes and the inheritance of alleles at the polymorphic NAT locus. Folate is confirmed to be an inhibitor of arylamine N-acetyltransferase activity measured in erythrocytes. The content of folate in erythrocytes of individuals also varies. The individual with the maximum folate content has the minimum N-acetyltransferase activity. The monomorphic N-acetyltransferase gene from individuals spanning the range of N-acetyltransferase activity have been amplified, using the polymerase chain reaction. The pattern of restriction enzyme digestion of the monomorphic N-acetyltransferase gene with a series of eight restriction enzymes is the same for individuals spanning the activity range of arylamine N-acetyltransferase in their erythrocytes.     

Effects of berberine on arylamine N-acetyltransferase activity in human bladder tumour cells.

Berberine was used to determine inhibition of arylamine N-acetyltransferase (NAT) activity in human bladder tumour cells. The NAT activity was measured by HPLC assaying for the amounts of N-acetyl-2-aminofluorene (AAF) and N-acetyl-p-aminobenzoic acid (N-Ac-PABA) and remaining 2-aminofluorene (AF) and p-aminobenzoic acid (PABA). Two assay systems were performed, one with cellular cytosols, the other with intact bladder tumour cell suspensions. The NAT activity in human bladder tumour cells was inhibited by berberine in a dose-dependent manner, that is, the higher the concentration of berberine, the higher the inhibition of NAT activity. The values of apparent Km and Vmax calculated from cytosol NAT and intact cells were also decreased by berberine. This report is the first demonstration to show berberine did affect human bladder tumour cell NAT activity.     

Extrahepatic expression of N-acetylator genotype in the inbred hamster

The genetic control of S-acetylcoenzyme A (AcCoA)-dependent N-acetyltransferase activity (EC 2.3.1.5) was investigated in liver, intestine, kidney, and lung cytosols derived from homozygous rapid acetylator (Bio. 87.20), heterozygous acetylator (Bio. 87.20 X 82.73/H F1), and homozygous slow acetylator (Bio. 82.73/H) Syrian inbred hamsters. AcCoA-dependent N-acetyltransferase activity was highest in hepatic cytosol, followed by intestine, kidney, and lung cytosol. In each of these tissues, cytosolic N-acetyltransferase exhibited an acetylator genotype-dependent activity with highest levels in homozygous rapid, intermediate levels in heterozygous F1 progeny, and lowest levels in homozygous slow acetylators. The ratio of N-acetyltransferase activity between acetylator genotypes was in general substrate dependent but not tissue dependent. Acetylator genotype-dependent N-acetyltransferase activity differences were highest for p-aminobenzoic acid, followed by p-aminosalicylic acid, 2-aminofluorene, and beta-naphthylamine. Expression of isoniazid N-acetyltransferase activity in each tissue was acetylator genotype independent. Determination of Michaelis-Menten kinetic constants in each tissue suggested that p-aminobenzoic acid N-acetyltransferase activity was acetylator genotype-dependent because of catalysis by an isozyme(s) that is both an apparent Km and a Vmax variant. In contrast, the acetylator genotype-independent expression of isoniazid N-acetyltransferase activity in each tissue appeared to result from a common isozyme(s) present in each tissue with equivalent kinetic constants in the two phenotypes. These data suggest that acetylator genotype-dependent expression of AcCoA-dependent N-acetyltransferase activity in extrahepatic tissues may play an important role in hereditary predisposition to toxicity and/or carcinogenesis in extrahepatic organs following exposure to arylamine drugs and foreign chemicals.     

4-Aminobiphenyl Downregulation of NAT2 Acetylator Genotype-Dependent N- and O-acetylation of Aromatic and Heterocyclic Amine Carcinogens in Primary Mammary Epithelial Cell Cultures from Rapid and Slow Acetylator Rats

Aromatic and heterocyclic amine carcinogens present in the dietand in cigarette smoke induce breast tumors in rats. N-acetyltransferase1 (NAT1) and N-acetyltransferase 2 (NAT2) enzymes have importantroles in their metabolic activation and deactivation. Humanepidemiological studies suggest that genetic polymorphisms inNAT1 and/or NAT2 modify breast cancer risk in women exposedto these carcinogens. p-Aminobenzoic acid (selective for ratNAT2) and sulfamethazine (SMZ; selective for rat NAT1) N-acetyltransferasecatalytic activities were both expressed in primary culturesof rat mammary epithelial cells. PABA, 2-aminofluorene, and4-aminobiphenyl N-acetyltransferase and N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and N-hydroxy-2-amino-3,8-dimethylimidazo[4,5-f]quinoxalineO-acetyltransferase activities were two- to threefold higherin mammary epithelial cell cultures from rapid than slow acetylatorrats. In contrast, SMZ (a rat NAT1-selective substrate) N-acetyltransferaseactivity did not differ between rapid and slow acetylators.Rat mammary cells cultured in the medium supplemented 24 h with10µM ABP showed downregulation in the N-and O-acetylationof all substrates tested except for the NAT1-selective substrateSMZ. This downregulation was comparable in rapid and slow NAT2acetylators. These studies clearly show NAT2 acetylator genotype–dependentN- and O-acetylation of aromatic and heterocyclic amine carcinogensin rat mammary epithelial cell cultures to be subject to downregulationby the arylamine carcinogen ABP.     

Effect of H2-receptor antagonists on rat liver cytosolic acetyl CoA:arylamine N-acetyltransferase activity.

This investigation examined the effect of cimetidine, famotidine, and ranitidine on rat liver acetyl CoA:arylamine N-acetyltransferase (NAT) activity. Studies were conducted using procainamide and p-aminobenzoic acid as substrate probes for NAT isozymes II and I, respectively. At an inhibitor:substrate ratio of 2:1, ranitidine, cimetidine, and famotidine reduced NAT II activity by 9, 48, and 75%, respectively. At this same ratio, none of the H2-receptor antagonists significantly reduced NAT I activity. The inhibition of NAT II activity by cimetidine and famotidine was mixed in nature, with characteristics consistent with predominantly competitive inhibitors. Preincubation of NAT with acetyl CoA did not attenuate the inhibitory effects of famotidine, suggesting this agent does not associate with the sulfhydryl of the critical cysteine residue on NAT. These results indicate the ability of H2-receptor antagonists to inhibit NAT activity with some degree of specificity for the two isozymes and significant differences in inhibitory potency between the antagonists.     

Luteolin-inhibited arylamine N-acetyltransferase activity and DNA-2-aminofluorene adduct in human and mouse leukemia cells.

N-Acetyltransferase enzyme is an important enzyme in the first step of arylamine compounds metabolism. Luteolin has been shown to exit antibacterial and antineoplastic activity. The purpose of this present study is to evaluate the question of whether luteolin could affect arylamine N-acetyltransferase (NAT) activity and DNA-2-aminofluorene adduct formation in human (HL-60) and mouse (L1210) leukemia cells. By using HPLC, N-acetylation of 2-aminofluorene was determined. Luteolin displayed a dose-dependent inhibition to cytosolic NAT activity and intact human and mice leukemia cells. Time-course experiments showed that N-acetylation of 2-aminofluorene measured from intact human and mice leukemia cells were inhibited by luteolin for up to 24 hours. Using standard steady-state kinetic analysis, it was demonstrated that luteolin was a possible uncompetitive inhibitor to NAT activity in cytosols. The DNA-2-aminofluorene adduct formation in human and mouse leukemia cells were inhibited by luteolin. This report is the first demonstration to show that luteolin affects human and mice leukemia cells NAT activity and DNA-2-aminofluorene on adduct formation.     

N-乙酰转移酶的多态性及其对肿瘤风险性的影响

N-乙酰转移酶是Ⅱ相药物代谢酶,在人体内由两个不同的基因编码,产生两个同酶NAT1和NAT2。NAT2的表达具有多态性,其慢乙酰化表型为NAT2基因编码区点突变所致。NAT1亦具有基因结构上的变异,不同的突变等位基因其酶表达水平不同。生化学研究表明NAT1和NAT2在致癌物质的代谢激活或灭活过程中起重要作用。流行病学研究则提示NATs的多态性与某些肿瘤的风险性有关,代谢基因型/表现型将通过影响DNA结合物的水平进而影响肿瘤的发生。如果肿瘤的遗传易感性这一生物标记能够成功地建立起来,将有助于更好地预防和控制人类疾病。