Department of Pharmacology & Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Environ Mol Mutagen. 2012 Jun;53(5):350-7. doi: 10.1002/em.21695. Epub 2012 Apr 17.
One model for cancer initiation by 4-aminobiphenyl (ABP) involves N-oxidation by cytochrome P450 CYP1A2 followed by O-conjugation by N-acetyltransferase(s) NAT1 and/or NAT2 and decomposition to a DNA-binding nitrenium ion. We recently observed that neonatal ABP exposure produced liver tumors in male but not in female mice, and that NAT deficiency reduced liver tumor incidence. However, ABP-induced liver tumor incidence did not correlate with liver levels of N-(deoxyguanosin-8-yl)-ABP adducts 24 hr after exposure. In this study, we compared in vivo ABP-induced DNA mutant frequencies and spectra between male and female wild-type and NAT-deficient Muta™Mouse using both the tumor-inducing neonatal exposure protocol and a 28-day repetitive dosing adult exposure protocol. ABP produced an increase in liver DNA mutant frequencies in both neonates and adults. However, we observed no sex or strain differences in mutant frequencies in neonatally exposed mice, and higher frequencies in adult females than males. Neonatal ABP exposure of wild-type mice increased the proportion of G-T transversions in both males and females, while exposure of Nat1/2(-/-) mice produced increased G-T transversions in males and a decrease in females, even though females had higher levels of N-(deoxyguanosin-8-yl)-4-ABP adducts. There was no correlation of mutant frequencies or spectra between mice dosed as neonates or as adults. These results suggest that observed sex- and NAT-dependent differences in ABP-induced liver tumor incidence in mice are not due to differences in either mutation rates or mutational spectra, and that mechanisms independent of carcinogen bioactivation, covalent DNA binding and mutation may be responsible for these differences.
一种涉及细胞色素 P450 CYP1A2 的 N-氧化、N-乙酰转移酶（NAT1 和/或 NAT2）的 O-共轭以及分解为与 DNA 结合的亚硝鎓离子的 4-氨基联苯（ABP）致癌起始模型。我们最近观察到，新生 AB 暴露会导致雄性而非雌性小鼠产生肝肿瘤，并且 NAT 缺乏会降低肝肿瘤的发生率。然而，ABP 诱导的肝肿瘤发生率与暴露后 24 小时肝内 N-(脱氧鸟嘌呤-8-基)-ABP 加合物水平无关。在这项研究中，我们比较了雄性和雌性野生型和 NAT 缺陷型 Muta™Mouse 在使用诱导肿瘤的新生暴露方案和 28 天重复剂量成年暴露方案时，体内 ABP 诱导的 DNA 突变频率和图谱。ABP 导致新生和成年动物的肝 DNA 突变频率增加。然而，我们在新生暴露的小鼠中没有观察到性别或品系差异的突变频率，并且成年雌性的频率高于雄性。新生 AB 暴露增加了雄性和雌性中 G-T 颠换的比例，而 Nat1/2(-/-) 小鼠的暴露增加了雄性中的 G-T 颠换并减少了雌性，尽管雌性具有更高水平的 N-(脱氧鸟嘌呤-8-基)-4-ABP 加合物。在新生或成年时给药的小鼠之间，突变频率或图谱没有相关性。这些结果表明，在小鼠中观察到的 AB 诱导肝肿瘤发生率的性别和 NAT 依赖性差异不是由于突变率或突变谱的差异引起的，并且可能与致癌物生物活化、共价 DNA 结合和突变无关的机制可能是导致这些差异的原因。
