Vater S T, Baldwin D M, Warshawsky D
Department of Environmental Health, Kettering Laboratory, University of Cincinnati Medical Center, Ohio 45267-0056.
Cancer Res. 1991 Jan 15;51(2):492-8.
Dimethylbenz(a)anthracene (DMBA) is a potent inducer of mammary tumors in intact female Sprague-Dawley rats, but not in males or ovariectomized females (OVX). Qualitative and quantitative aspects of hepatic metabolism of DMBA were examined in these three groups of rats, using the nonrecirculating perfused liver, to determine whether the production of proximate carcinogenic metabolites of DMBA by the liver differed among these groups in the same manner as does sensitivity to tumor induction. DMBA was infused into the liver at a constant rate for 60 min. Rates of appearance of DMBA and its metabolites were measured in perfusate and bile during the infusion period and the first 60 min thereafter. The maximum rate of appearance of total metabolites in the perfusate, seen at the end of the infusion period, was highest in the intact female [2.6 +/- 0.3 nmol/(g x min)], slightly lower in the OVX [2.3 +/- 0.2 nmol/(g x min)] and significantly lower in the male [1.0 +/- 0.1 nmol/(g x min)]. The rates of appearance of metabolites in the bile showed the same order as those seen in the perfusate. The major metabolites extracted from the perfusate in all three groups were dihydrodiols, hydroxymethyl metabolites, and several unidentified metabolites. The 3,4-dihydrodiol, a proximate carcinogenic metabolite, appeared in the perfusate at higher rates in the intact female and OVX than in the male. Hydrolysis of bile samples showed that glucuronidation was a major pathway in the excretion of DMBA metabolites in bile. High performance liquid chromatographic analysis indicated that hydrolysis of DMBA glucuronides yielded the 7- and 12-hydroxymethyl metabolites and an unidentified metabolite designated X. The major hydrolysis product in the male was 12-hydroxymethyl while X was found to be the major product in the intact female and OVX. Under the conditions of this study, there were differences in the metabolic activation of DMBA by male and female rat liver. Ovariectomy, followed by DMBA perfusion 7 days later, did not result in significant changes in DMBA metabolism relative to the intact female, except for a decreased rate of excretion of metabolites in bile.
二甲基苯并(a)蒽(DMBA)是完整雌性斯普拉格-道利大鼠乳腺肿瘤的强效诱导剂，但对雄性大鼠或去卵巢雌性大鼠(OVX)无效。使用非循环灌注肝脏，在这三组大鼠中研究了DMBA肝脏代谢的定性和定量方面，以确定肝脏产生的DMBA近致癌物代谢物在这些组中是否与对肿瘤诱导的敏感性以相同方式存在差异。以恒定速率将DMBA注入肝脏60分钟。在注入期间及其后的前60分钟内，测量灌注液和胆汁中DMBA及其代谢物的出现速率。在注入期结束时，灌注液中总代谢物的最大出现速率在完整雌性大鼠中最高[2.6±0.3 nmol/(g·min)]，在去卵巢雌性大鼠中略低[2.3±0.2 nmol/(g·min)]，在雄性大鼠中显著更低[1.0±0.1 nmol/(g·min)]。胆汁中代谢物的出现速率与灌注液中的顺序相同。从所有三组灌注液中提取的主要代谢物是二氢二醇、羟甲基代谢物和几种未鉴定的代谢物。近致癌物代谢物3,4-二氢二醇在完整雌性大鼠和去卵巢雌性大鼠的灌注液中出现的速率高于雄性大鼠。胆汁样品的水解表明，葡萄糖醛酸化是胆汁中DMBA代谢物排泄的主要途径。高效液相色谱分析表明，DMBA葡萄糖醛酸苷的水解产生了7-和12-羟甲基代谢物以及一种未鉴定的代谢物X。雄性大鼠中的主要水解产物是12-羟甲基，而X是完整雌性大鼠和去卵巢雌性大鼠中的主要产物。在本研究条件下，雄性和雌性大鼠肝脏对DMBA的代谢活化存在差异。去卵巢7天后进行DMBA灌注，相对于完整雌性大鼠，DMBA代谢没有显著变化，只是胆汁中代谢物的排泄速率降低。
