Wong A K, Cavalieri E, Rogan E
Chem Biol Interact. 1986 Jul-Aug;59(1):113-26. doi: 10.1016/s0009-2797(86)80058-8.
The metabolic profile of benzo[a]pyrene (BP) in cumene hydroperoxide-(CHP)-dependent reaction by male rat liver microsomes was dependent on CHP concentration. At 0.05 mM CHP, 3-hydroxy-BP was the major metabolite. Increase in CHP reduced 3-hydroxy-BP formation but increased BP quinone formation simultaneously. This change in metabolic profile was reversed by preincubation with pyrene. Pyrene (PY) selectively inhibited quinone formation but enhanced 3-hydroxy-BP formation. Naphthalene (NP) had no effect on BP quinone formation but inhibited BP 3-hydroxylation. Phenanthrene (PA) and benz[a]anthracene (BA) inhibited effectively 3-hydroxy-BP formation but only slightly quinone formation. BP binding to microsomal protein correlated to quinone formation and not BP 3-hydroxylation. BP metabolism by female rat liver microsomes also depended on CHP concentration but was much less efficient than the male. Quinones were consistently predominant metabolites and their formation was also inhibited by pyrene. Our data provide evidence that regioselectivity in BP metabolism involves at least two distinct binding sites. One site recognizes the benzo region of BP in BP 3-hydroxylation and the other recognizes the pyrene region in quinone formation. The different ratios of 3-hydroxy-BP to quinone formation by male and female rat liver microsomes suggest that the two binding sites are probably located at separate cytochrome P-450 isozymes.
雄性大鼠肝微粒体在氢过氧化异丙苯（CHP）依赖性反应中对苯并[a]芘（BP）的代谢谱取决于CHP浓度。在0.05 mM CHP时，3-羟基-BP是主要代谢产物。CHP浓度增加会减少3-羟基-BP的形成，但同时会增加BP醌的形成。用芘预孵育可逆转这种代谢谱的变化。芘（PY）选择性抑制醌的形成，但增强3-羟基-BP的形成。萘（NP）对BP醌的形成没有影响，但抑制BP的3-羟基化。菲（PA）和苯并[a]蒽（BA）有效抑制3-羟基-BP的形成，但仅轻微抑制醌的形成。BP与微粒体蛋白的结合与醌的形成相关，而与BP的3-羟基化无关。雌性大鼠肝微粒体对BP的代谢也取决于CHP浓度，但效率远低于雄性。醌始终是主要代谢产物，芘也会抑制其形成。我们的数据提供了证据，表明BP代谢中的区域选择性涉及至少两个不同的结合位点。一个位点在BP的3-羟基化过程中识别BP的苯并区域，另一个位点在醌的形成过程中识别芘区域。雄性和雌性大鼠肝微粒体中3-羟基-BP与醌形成的不同比例表明，这两个结合位点可能位于不同的细胞色素P-450同工酶上。
