Colby H D, Johnson P B, Pope M R, Zulkoski J S
Biochem Pharmacol. 1982 Mar 1;31(5):639-46. doi: 10.1016/0006-2952(82)90443-9.
Studies were carried out to compare the metabolism of benzo [a] pyrene (BP) by adrenal and hepatic microsomes obtained from adult male guinea pigs. Adrenal microsomes produced fluorescent metabolites (primarily phenols) approximately three to four times more rapidly than hepatic microsomes, but the differences in the rates were considerably smaller when total BP metabolism was assessed using an isotopic assay. The apparent discrepancy between the two assays is attributable to differences in the profiles of BP metabolites produced by adrenal and liver. Separation of metabolites by high pressure liquid chromatography revealed that adrenal microsomes converted BP to primarily a phenolic metabolite with a retention time identical to that of 3-hydroxy-BP. Liver microsomes, by contrast, produced approximately equal amounts of compounds co-chromatographing with 3-hydroxy-BP and BP-4,5-dihydrodiol. Small amounts of other metabolites were also produced by adrenal and hepatic microsomes. Liver microsomes catalyzed the conversion of BP to metabolites that became covalently bound to exogenous DNA. The amount of binding was dependent upon the duration of incubation and concentration of microsomal protein. Adrenal microsomes, by contrast, did not promote BP binding to DNA. Inhibition of microsomal epoxide hydratase activity with trichloropropene oxide (TCPO) blocked the formation of dihydrodiol metabolites of BP by adrenal and liver microsomes. In the presence of TCPO, liver microsomes produced large amounts of a BP metabolite co-chromatographing with BP-4,5-oxide. TCPO also increased the rate of production of DNA-binding metabolites by liver microsomes but had no effect on the formation of DNA-binding metabolites by adrenal microsomes. The results demonstrate major differences in the pathways of BP metabolism by guinea pig adrenal and hepatic microsomes. Although adrenal microsomes metabolize BP more rapidly than hepatic microsomes, far greater amounts of reactive metabolites are produced by the liver. Thus, adrenal metabolism of BP may be of little toxicological significance.
开展了多项研究，以比较成年雄性豚鼠肾上腺和肝脏微粒体对苯并[a]芘（BP）的代谢情况。肾上腺微粒体产生荧光代谢物（主要是酚类）的速度比肝脏微粒体快约三到四倍，但使用同位素分析法评估总BP代谢时，两者的速率差异要小得多。两种分析方法之间明显的差异归因于肾上腺和肝脏产生的BP代谢物谱不同。通过高压液相色谱法分离代谢物发现，肾上腺微粒体将BP主要转化为一种保留时间与3-羟基-BP相同的酚类代谢物。相比之下，肝脏微粒体产生的与3-羟基-BP和BP-4,5-二氢二醇共色谱的化合物量大致相等。肾上腺和肝脏微粒体也产生少量其他代谢物。肝脏微粒体催化BP转化为与外源性DNA共价结合的代谢物。结合量取决于孵育时间和微粒体蛋白浓度。相比之下，肾上腺微粒体不促进BP与DNA的结合。用三氯丙烯氧化物（TCPO）抑制微粒体环氧化物水解酶活性可阻断肾上腺和肝脏微粒体对BP二氢二醇代谢物的形成。在TCPO存在下，肝脏微粒体产生大量与BP-4,5-氧化物共色谱的BP代谢物。TCPO还增加了肝脏微粒体产生DNA结合代谢物的速率，但对肾上腺微粒体形成DNA结合代谢物没有影响。结果表明豚鼠肾上腺和肝脏微粒体对BP的代谢途径存在重大差异。尽管肾上腺微粒体代谢BP的速度比肝脏微粒体快，但肝脏产生的活性代谢物数量要多得多。因此，BP的肾上腺代谢可能在毒理学上意义不大。
