Viswanathan T, Alworth W L
J Med Chem. 1981 Jul;24(7):822-30. doi: 10.1021/jm00139a011.
The inhibitions of cytochrome P-450 dependent monooxygenase activity in microsomes from rat liver by 1-phenylpyrrole, 1-(2-isopropylphenyl)pyrrole, 4(5)-phenylimidazole, and 1-(2-isopropylphenyl)imidazole have been compared. The results establish that the presence of an imidazole N-3 nitrogen substituent is not required to inhibit the monooxygenase activity measured by the deethylation of 7-ethoxycoumarin. The presence of an appropriately situated N-3 atom, however, as in 1-(2-isopropylphenyl)imidazole, significantly decreases both the Ki and alphaKi of these mixed type inhibitors. The induction of 7-ethoxycoumarin deethylase activity in the microsomal fraction from rat liver by alpha-naphthoflavone, beta-naphthoflavone, and 3-methylcholanthrene and the inhibition of these activities by flavone and alpha-, beta, and gamma-naphthoflavone have also been examined. The results establish that alpha-naphthoflavone is the most effective in vitro inhibitor. The results also indicate that the microsomal monooxygenase activities induced in rat liver by alpha-naphthoflavone, beta-naphthoflavone, and 3-methylcholanthrene are not equivalent. Based upon the observed results, it is concluded that differential effects of alpha- and beta-naphthoflavone on aryl hydrocarbon skin tumorigenesis may be the result of differential enzyme induction rather than the result of differential enzyme inhibition.
比较了1-苯基吡咯、1-(2-异丙基苯基)吡咯、4(5)-苯基咪唑和1-(2-异丙基苯基)咪唑对大鼠肝脏微粒体中细胞色素P-450依赖性单加氧酶活性的抑制作用。结果表明，抑制由7-乙氧基香豆素脱乙基作用测定的单加氧酶活性并不需要咪唑N-3位有氮取代基。然而，像在1-(2-异丙基苯基)咪唑中那样，一个位置合适的N-3原子的存在，会显著降低这些混合型抑制剂的Ki和αKi。还研究了α-萘黄酮、β-萘黄酮和3-甲基胆蒽对大鼠肝脏微粒体部分中7-乙氧基香豆素脱乙基酶活性的诱导作用，以及黄酮和α-、β-、γ-萘黄酮对这些活性的抑制作用。结果表明，α-萘黄酮是最有效的体外抑制剂。结果还表明，α-萘黄酮、β-萘黄酮和3-甲基胆蒽在大鼠肝脏中诱导的微粒体单加氧酶活性并不相同。基于观察结果，得出结论：α-和β-萘黄酮对芳烃皮肤肿瘤发生的不同影响可能是酶诱导差异的结果，而不是酶抑制差异的结果。
