Al-Buheissi Salah Z, Patel Hiten R, Meinl Walter, Hewer Alan, Bryan Richard L, Glatt Hansruedi, Miller Ronald A, Phillips David H
Institute of Cancer Research, Section of Molecular Carcinogenesis, Sutton, UK.
Pharmacogenet Genomics. 2006 Jun;16(6):391-9. doi: 10.1097/01.fpc.0000204998.22301.09.
N-Acetyltransferases (NATs) and sulfotransferases (SULTs) are key phase II metabolizing enzymes that can be involved both in the detoxification and in the activation of many human promutagens and procarcinogens.
We investigated the expression of NATs and SULTs in human prostate and tested their role in the activation the N-hydroxy (N-OH) metabolite of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), a dietary carcinogen, to form DNA adducts. Western blotting showed detectable levels of NAT1, SULT1A1 and SULT1A3 with marked inter-individual variation. NAT2 and other SULT enzymes were not detectable. NAT1 was localized by immunohistochemistry to the cytoplasm of epithelial cells. The presence of acetyl Co-enzyme A (acetyl CoA) and 3'-phosphoadenosine-5'-phosphosulfate (PAPS), NAT and SULT cofactors, respectively, significantly increased the level of DNA adducts, detected by P-postlabelling analysis, in calf thymus DNA incubated with N-OH-IQ and prostate cytosolic fractions. The enhancement in the level of DNA adducts in the presence of PAPS correlated with the level of SULT1A1 protein. A single prostate cytosol with the SULT1A1*2/*2 genotype produced less DNA adducts than cytosols with the *1/*2 and *1/*1 genotypes. No significant correlation was observed between NAT1 protein level and the formation of DNA adducts, even in the presence of acetyl CoA.
In conclusion, we demonstrated that NAT1, SULT1A1 and SULT1A3 are present in human prostate and that both enzyme classes significantly contribute to the activation of N-hydroxylated heterocyclic amines to DNA-damaging species in this tissue. Variation in expression levels, in combination with dietary and/or environmental exposure to carcinogens, could be influential in determining individual susceptibility to prostate cancer.
N-乙酰基转移酶（NATs）和磺基转移酶（SULTs）是关键的II期代谢酶，可参与多种人类前诱变剂和前致癌物的解毒与活化过程。
我们研究了NATs和SULTs在人前列腺中的表达，并测试了它们在将膳食致癌物2-氨基-3-甲基咪唑[4,5-f]喹啉（IQ）的N-羟基（N-OH）代谢产物活化为DNA加合物过程中的作用。蛋白质印迹法显示可检测到NAT1、SULT1A1和SULT1A3的水平，个体间差异显著。未检测到NAT2和其他SULT酶。通过免疫组织化学法将NAT1定位于上皮细胞的细胞质中。分别作为NAT和SULT辅助因子的乙酰辅酶A（acetyl CoA）和3'-磷酸腺苷-5'-磷酸硫酸酯（PAPS）的存在，显著增加了用P-后标记分析法检测到的、与N-OH-IQ和前列腺胞质组分一起孵育的小牛胸腺DNA中的DNA加合物水平。PAPS存在时DNA加合物水平的增强与SULT1A1蛋白水平相关。具有SULT1A1*2/2基因型的单个前列腺胞质溶胶产生的DNA加合物比具有1/2和1/*1基因型的胞质溶胶少。即使在存在乙酰辅酶A的情况下，NAT1蛋白水平与DNA加合物的形成之间也未观察到显著相关性。
总之，我们证明NAT1、SULT1A1和SULT1A3存在于人前列腺中，并且这两类酶在该组织中均对N-羟基化杂环胺活化为DNA损伤物种有显著贡献。表达水平的变化，结合饮食和/或环境致癌物暴露，可能对确定个体对前列腺癌的易感性有影响。
