Kandaswami C, Kumar S, Dubey S K, Sikka H C
Great Lakes Laboratory, State University of New York College, Buffalo 14222.
Carcinogenesis. 1987 Dec;8(12):1861-6. doi: 10.1093/carcin/8.12.1861.
The metabolism of [1,3-14C]benzo[f]quinoline (BfQ) by liver microsomes from control, 3-methylcholanthrene (3-MC)-pretreated and phenobarbital (PB)-pretreated rats has been investigated in order to gain insights into the effect of mixed function oxidase inducers on the types and levels of specific metabolites as formed in vitro. The rates of metabolism of BfQ by liver microsomes from control, 3-MC- and PB-pretreated rats were 0.5, 3.6 and 2.4 nmol/min/mg of respectively. The most predominant metabolite of BfQ detected with liver microsomes from 3-MC-pretreated rats was BfQ-7,8-dihydrodiol, a precursor of the bay-region diol epoxide, constituting 41% of the total ethyl acetate-extractable metabolites. Other metabolites obtained along with their relative proportions were as follows: BfQ-N-oxide, 23% 7-hydroxyBfQ, 15%; 9-hydroxyBfQ, 9%; and BfQ-9,10-dihydrodiol, 6%. BfQ-5,6-dihydrodiol, a K-region dihydrodiol, was a trace metabolite representing approximately 1.0% of the total metabolism. Liver microsomes from PB-pretreated rats oxidized BfQ primarily to BfQ-N-oxide and 9-hydroxyBfQ, which constituted 41% and 20% of the total ethyl acetate-extractable metabolites of BfQ. The relative proportions of BfQ-9,10-dihydrodiol, BfQ-7,8-dihydrodiol and 7-hydroxy-BfQ formed were 12%, 3% and 13% respectively, while the figure for BfQ-5,6-dihydrodiol was 0.5%. The profile of metabolites formed by liver microsomes from control rats was similar to that generated by microsomes from PB-pretreated rats. While benzo-ring metabolites represented a major part of the metabolism of BfQ by liver microsomes from either 3-MC- or PB-pretreated rats, these two types of microsomes exhibited a positional selectivity in the oxidation of BfQ, the former primarily attacking the 7,8-position of BfQ while the latter preferentially oxidizing the 9,10-position. The preponderance of the potentially mutagenic BfQ-7,8-dihydrodiol amongst the metabolites generated by liver microsomes from 3-MC-pretreated rats suggests a possible role for cytochrome P-450c, the major form of rat hepatic cytochrome P-450 induced by 3-MC, in the metabolic activation of BfQ.
为了深入了解混合功能氧化酶诱导剂对体外形成的特定代谢产物类型和水平的影响，研究了对照大鼠、经3-甲基胆蒽（3-MC）预处理的大鼠和经苯巴比妥（PB）预处理的大鼠肝脏微粒体对[1,3-¹⁴C]苯并[f]喹啉（BfQ）的代谢情况。对照大鼠、经3-MC预处理的大鼠和经PB预处理的大鼠肝脏微粒体对BfQ的代谢速率分别为0.5、3.6和2.4 nmol/分钟/毫克。用经3-MC预处理的大鼠肝脏微粒体检测到的BfQ最主要代谢产物是BfQ-7,8-二氢二醇，它是湾区二醇环氧化物的前体，占乙酸乙酯可提取代谢产物总量的41%。其他代谢产物及其相对比例如下：BfQ-N-氧化物，23%；7-羟基BfQ，15%；9-羟基BfQ，9%；以及BfQ-9,10-二氢二醇，6%。BfQ-5,6-二氢二醇，一种K区二氢二醇，是微量代谢产物，约占总代谢量的1.0%。经PB预处理的大鼠肝脏微粒体将BfQ主要氧化为BfQ-N-氧化物和9-羟基BfQ，它们分别占BfQ乙酸乙酯可提取代谢产物总量的41%和20%。形成的BfQ-9,10-二氢二醇、BfQ-7,8-二氢二醇和7-羟基BfQ的相对比例分别为12%、3%和13%，而BfQ-5,6-二氢二醇的比例为0.5%。对照大鼠肝脏微粒体形成的代谢产物谱与经PB预处理的大鼠微粒体产生的谱相似。虽然苯环代谢产物是经3-MC或PB预处理的大鼠肝脏微粒体对BfQ代谢的主要部分，但这两种类型的微粒体在BfQ氧化过程中表现出位置选择性，前者主要攻击BfQ的7,8位，而后者优先氧化9,10位。经3-MC预处理的大鼠肝脏微粒体产生的代谢产物中潜在致突变性的BfQ-7,8-二氢二醇占优势，这表明大鼠肝脏细胞色素P-450的主要形式——由3-MC诱导的细胞色素P-450c，在BfQ的代谢活化中可能起作用。
