Carlson G P, Hynes D E, Mantick N A
School of Health Sciences, Purdue University, West Lafayette, IN 47907-1338, USA.
Toxicol Lett. 1998 Sep 15;98(3):131-7. doi: 10.1016/s0378-4274(98)00111-8.
Much of the toxicity of styrene is associated with its bioactivation to styrene oxide. Both liver and lung have been shown to carry out this metabolic step, but there are differences reported as to which isomers of cytochrome P450 are responsible for this biotransformation in various species and tissues. CYP2E1, CYP2F, CYP2B, CYP1A1/2 and CYP2C11 have all been implicated. In the current study, alpha-naphthoflavone (alphaNF) and alpha-methylbenzylaminobenzotriazole (MBA), selective inhibitors of CYP1A and CYP2B, were used to ascertain the contributions of these isomers to styrene metabolism in mouse hepatic and pulmonary microsomes. AlphaNF did not inhibit styrene metabolism with microsomal preparations from either tissue. This indicates that CYP1A is unimportant in the metabolism of styrene to styrene oxide. MBA at a very low concentration of 1 microM inhibited the hepatic metabolism of benzyloxyresorufin (a CYP2B substrate) by 87% but caused only a 16 to 19% inhibition of R- and S-styrene oxide formation. This demonstrates that CYP2B plays a minor role in styrene metabolism. At 10 microM, MBA caused an even greater inhibition of styrene metabolism but at that level it also inhibited p-nitrophenol hydroxylation, a CYP2E1-dependent reaction, suggesting a loss of selectivity for this inhibitor at higher concentrations.
苯乙烯的许多毒性都与其生物活化生成环氧苯乙烯有关。肝脏和肺都已被证明能进行这一代谢步骤，但关于细胞色素P450的哪些异构体在不同物种和组织中负责这种生物转化，有不同的报道。CYP2E1、CYP2F、CYP2B、CYP1A1/2和CYP2C11都被认为与此有关。在本研究中，使用CYP1A和CYP2B的选择性抑制剂α-萘黄酮（αNF）和α-甲基苄基氨基苯并三唑（MBA）来确定这些异构体对小鼠肝脏和肺微粒体中苯乙烯代谢的贡献。αNF对来自任何一种组织的微粒体制剂的苯乙烯代谢均无抑制作用。这表明CYP1A在苯乙烯代谢生成环氧苯乙烯的过程中并不重要。浓度低至1微摩尔的MBA可使苄氧基试卤灵（一种CYP2B底物）的肝脏代谢受到87%的抑制，但仅使R-和S-环氧苯乙烯生成受到16%至19%的抑制。这表明CYP2B在苯乙烯代谢中起次要作用。在10微摩尔时，MBA对苯乙烯代谢的抑制作用更强，但在该浓度下它也抑制了对硝基苯酚羟基化反应（一种CYP2E1依赖性反应），这表明该抑制剂在较高浓度下失去了选择性。
