Johansson M, Larsson C, Bergman A, Lund B O
Department of Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Uppsala, Sweden.
Pharmacol Toxicol. 1998 Nov;83(5):225-30. doi: 10.1111/j.1600-0773.1998.tb01473.x.
The effects of xenobiotics on CYP11B1-dependent corticosterone synthesis (11 beta-hydroxylase) in mouse adrenocortical Y1 cells were studied. 3-Methylsulfonyl-2,2-bis(4-chlorophenyl)-1,1-dichloroethene (MeSO2-DDE) and some methylsulfonyl polychlorinated biphenyls (MeSO2-PCB) inhibited the corticosterone synthesis, whereas PCBs or DDE did not. This indicates a crucial role of the methyl sulfone group for this inhibitory effect. Kinetic analyses of MeSO2-DDE and the two most potent MeSO2-PCBs were conducted using Lineweaver-Burk double-reciprocal plots. The data showed a competitive inhibition of CYP11B1 by the compounds, with apparent inhibitory constants (Ki) of 1.6, 4.6, and 6.7 microM for MeSO2-DDE, 4-MeSO2-2,3,6,4'-tetrachlorobiphenyl, and 4-MeSO2-2,3,6,3',4'-pentachlorobiphenyl, respectively. For comparison, the substrate K(m) was 3.5 microM in the cells, and metyrapone and ketoconazole had apparent Ki-values of 0.8 and 0.04 microM, respectively. In contrast to all previously known inhibitors of CYP11B1, the aryl methyl sulfones are the first examples of CYP11B1 inhibitors not being heterocyclic amines or steroids. The aryl methyl sulfones are widespread environmental pollutants and their inhibition of CYP11B1 constitutes another potential mechanism for endocrine disruption. Their influence on the synthesis of adrenocortical hormones thus merits further interest.
研究了外源性物质对小鼠肾上腺皮质Y1细胞中细胞色素P450 11B1（CYP11B1）依赖性皮质酮合成（11β-羟化酶）的影响。3-甲基磺酰基-2,2-双（4-氯苯基）-1,1-二氯乙烯（MeSO2-DDE）和一些甲基磺酰基多氯联苯（MeSO2-PCB）可抑制皮质酮合成，而多氯联苯（PCB）或滴滴涕（DDE）则无此作用。这表明甲基砜基团对这种抑制作用起着关键作用。使用Lineweaver-Burk双倒数图对MeSO2-DDE和两种最有效的MeSO2-PCB进行了动力学分析。数据显示这些化合物对CYP11B1具有竞争性抑制作用，MeSO2-DDE、4-MeSO2-2,3,6,4'-四氯联苯和4-MeSO2-2,3,6,3',4'-五氯联苯的表观抑制常数（Ki）分别为1.6、4.6和6.7 microM。作为比较，细胞中的底物米氏常数（K(m)）为3.5 microM，美替拉酮和酮康唑的表观Ki值分别为0.8和0.04 microM。与所有先前已知的CYP11B1抑制剂不同，芳基甲基砜是CYP11B1抑制剂中首个不是杂环胺或类固醇的例子。芳基甲基砜是广泛存在的环境污染物，它们对CYP11B1的抑制作用构成了内分泌干扰的另一种潜在机制。因此，它们对肾上腺皮质激素合成的影响值得进一步关注。
