Association between polymorphisms at N-acetyltransferase 1 (NAT1) & risk of oral leukoplakia & cancer.

Background & objectives: N-acetyltransferases 1 and 2 (NAT1 and NAT2) are important enzymes for metabolism of tobacco carcinogens. Due to polymorphisms, improper activities of these enzymes might lead to the formation of DNA adducts that may modulate risk of tobacco related oral precancer and cancer. Previously, it was shown that NAT2 polymorphisms did not modulate the risk of oral precancer and cancer. We undertook this study to check whether polymorphisms at NAT1 can modulate the risk of oral leukoplakia and cancer either alone or in combination with NAT2. Methods: Genotypes at four SNPs on NAT1 were determined by TaqMan method in 389 controls, 224 leukoplakia and 310 cancer patients. Genotype data were analyzed to know haplotypes and acetylation status of individuals and, then to estimate the risk of diseases. Using our previously published NAT2 data, combination of NAT1 and NAT2 acetylation genotypes of patients and controls were also analyzed to estimate the risk of diseases. Results: Analysis of NAT1 genotype data revealed that 1088T and 1095C alleles exist in strong linkage disequilibrium (r2=0.97, P<0.0001) and SNPs are in Hardy-Weinberg Equilibrium (P=0.1). Wild type or normal acetylating and variant or rapid acetylating alleles were two major alleles (frequencies 0.62 and 0.36, respectively) present in the control population. NAT1 rapid acetylation could not modulate the risk of leukoplakia and cancer (OR=0.9, 95% CI: 0.6-1.3; OR=1.0, 95% CI: 0.7-1.4, respectively). Analysis of combined NAT1 and NAT2 acetylating data also showed no significant enhancement of the risk of diseases. Interpretation & conclusions: NAT1 rapid acetylation alone as well as combination of NAT1 rapid-NAT2 slow acetylation did not modulate the risk of oral precancer and cancer in our patient population. So, NAT1/NAT2 metabolized carcinogen products may not be involved in tobacco related oral precancer and cancer. It may be interpreted that large sample size as well as combination of polymorphisms at other candidate loci may be important to estimate the risk of a complex disease like oral cancer.

Effects of humulon on kinetic constants of NAT1 in SGC-7901 cells / 中草药

Objective To explore the effects of humulon on kinetic parameters of N-acetyltransferase-1(NAT1) of human gastric cancer SGC-7901.Methods Employing HPLC,using para-aminobenzoic acid(PABA) as substrate,in intact SGC-7901 cells and their cytoplasm,taking the speed of PABA being acetylated to Ac-PABA by NAT1 as the rate of NAT1,using double reciprocal plot,taking the reciprocal of concentration of PABA and reaction rate of NAT1 as coordinates,regression equation was obtainied and the Michaelis constant(Km) and maximum reaction velocity(Vmax) were calculated.Results Study on enzyme kinetics demonstrated,as for intact SGC-7901 cells,Km and Vmax of control group were(3.910?0.087) ?mol/L and(0.306 0?0.006 7) pmol/L(1?106 cells),respectively,Km and Vmax of the humulon group were(3.830?0.123) ?mol/L and(0.275 0?0.005 8) pmol(1?106 cells),respectively.As for the cytoplasm of SGC-7901 cells,Km and Vmax of control group were(760.2?210.2) ?mol/L and(0.191 0?0.043 7) pmol/(mg?min),Km and Vmax of the humulon group were(449.0?72.9) ?mol/L and(0.094 0?0.010 4) pmol/(mg?min).Statistically,as for intact SGC-7901 cells or their cytoplasm,there was no difference of the Km between control group and humulon group,but there was remarkable difference of Vmax between control group and humulon group,P

Inhibition of humulon on arylamine N-acetyltransferase-1 activity and gene expression in SGC-7901 cells / 中草药

Objective To study the anti-tumor effects of humulon on arylamine N-acetyltransferase-1(NAT1)activity.Methods Employing HPLC,using PABA as substrate,in intact SGC-7901 cells and their cytoplasm,making PABA being acetylated to Ac-PABA by NAT1 as the activity of NAT1.Reverse transcriptase polymerase chain reaction(RT-PCR)assay was used to study the expression of the NAT1 mRNA.Results The results show that humulon could inhibit the production of Ac-PABA in intact SGC-7901 cell and the cytoplasm,the production of Ac-PABA was gradually increased with the interaction time increasing.But comparing with corresponding negative control group's,the production of Ac-PABA was decreased evidently and the humulone could inhibit the expression of NAT1 mRNA.Conclusion Humulon could prevent the occurrence and deterioration of cancer.Its mechanisms can be attributed to its effect on decreasing the production of acetylation of carcinogenic aromatic amines,which is acetylated from aromatic amines,and inhibiting the NAT1 activity and expression of NAT1 mRNA.