McCallum G P, Horton J E, Falkner K C, Bend J R
Department of Pharmacology and Toxicology, University of Western Ontario, London, Canada.
Can J Physiol Pharmacol. 1993 Feb;71(2):151-6. doi: 10.1139/y93-021.
Characterization of cytochrome P450 1A1 dependent monooxygenases in guinea pig heart revealed low rates of 7-ethoxyresorufin O-deethylation, which are markedly increased (20-fold) by treatment with beta-naphthoflavone, a polycyclic aromatic hydrocarbon. Both 7-ethoxyresorufin O-deethylation and 7-methoxyresorufin O-demethylation were found to be approximately 4-fold higher in microsomes prepared from the ventricle than the atrium of beta-naphthoflavone-induced guinea pigs. The low rates of 7-ethoxyresorufin O-deethylation in cardiac microsomes were due, at least in part, to a deficiency of the flavoprotein NADPH--cytochrome P450 reductase; addition of exogenous NADPH--cytochrome P450 reductase; addition of exogenous NADPH--cytochrome P450 reductase dramatically increased 7-ethoxyresorufin O-deethylation in cardiac microsomes of guinea pigs, before and after treatment with beta-naphthoflavone. N-Benzyl-1-aminobenzotriazole, a suicide substrate of cytochrome P450 1A1 in guinea pig, was able to inhibit almost all of the 7-ethoxyresorufin O-deethylase and 7-methoxyresorufin O-demethylase activities in polycyclic aromatic hydrocarbon induced guinea pig heart (88 and 71%, respectively), suggesting that cytochrome P450 1A1 coupled to NADPH--cytochrome P450 reductase in these microsomes inactivates itself by a suicidal mechanism. Addition of alpha-naphthoflavone, an inhibitor of cytochrome P450 1A isozymes, to cardiac microsomes from beta-naphthoflavone-induced guinea pigs resulted in greater than 95% inhibition of 7-ethoxyresorufin O-deethylase activity. The biological significance of these low levels of cytochrome P450 1A1 monooxygenase activity in guinea pig heart and their induction by polycyclic aromatic hydrocarbons are not currently understood.
豚鼠心脏中细胞色素P450 1A1依赖性单加氧酶的特性研究表明，7-乙氧基异吩恶唑酮O-脱乙基反应速率较低，在用多环芳烃β-萘黄酮处理后，该反应速率显著提高（20倍）。在由β-萘黄酮诱导的豚鼠心室制备的微粒体中，7-乙氧基异吩恶唑酮O-脱乙基反应和7-甲氧基异吩恶唑酮O-脱甲基反应的速率均比心房制备的微粒体中约高4倍。心脏微粒体中7-乙氧基异吩恶唑酮O-脱乙基反应速率较低，至少部分原因是黄素蛋白NADPH-细胞色素P450还原酶缺乏；添加外源性NADPH-细胞色素P450还原酶后，无论是否用β-萘黄酮处理，豚鼠心脏微粒体中7-乙氧基异吩恶唑酮O-脱乙基反应均显著增加。N-苄基-1-氨基苯并三唑是豚鼠细胞色素P450 1A1的自杀性底物，能够抑制多环芳烃诱导的豚鼠心脏中几乎所有的7-乙氧基异吩恶唑酮O-脱乙基酶和7-甲氧基异吩恶唑酮O-脱甲基酶活性（分别为88%和71%），这表明在这些微粒体中，与NADPH-细胞色素P450还原酶偶联的细胞色素P450 1A1通过自杀机制使自身失活。向β-萘黄酮诱导的豚鼠心脏微粒体中添加细胞色素P450 1A同工酶抑制剂α-萘黄酮，可导致7-乙氧基异吩恶唑酮O-脱乙基酶活性受到大于95%的抑制。目前尚不清楚豚鼠心脏中这些低水平的细胞色素P450 1A1单加氧酶活性及其被多环芳烃诱导的生物学意义。
