Chinje E, Gibson G G
Biochemistry Department, University of Surrey, Guildford, U.K.
Biochem Pharmacol. 1991 Mar 1;41(5):769-74. doi: 10.1016/0006-2952(91)90079-k.
Induction of hepatic microsomal cytochrome P450IVA1 and peroxisomal enzymes of the beta-oxidation spiral were observed when male Long Evans hooded rats were administered optically pure enantiomeric forms and a racemic mixture of a clofibrate analogue [2-[4-(4-chlorophenyl)benzyloxy]-2-phenylacetic acid] at a dose level of 80 mg/kg for 3 days. The R(-)-enantiomer was found to be a more potent inducer of microsomal cytochrome P450IVA1 and its associated lauric acid 12-hydroxylase activity than its corresponding S(+)-antipode. This difference in potency was reflected by a eudismic ratio (R/S activity ratio) of approximately 3, whereas the racemic mixture exhibited a potency intermediary between the two isomers. An identical enantiomeric selectivity was observed for the phenomenon of peroxisome proliferation as judged by induction of cyanide-insensitive palmitoyl CoA oxidation and the bifunctional protein of the peroxisomal beta-oxidation spiral. The highest potency was shown by the R(-)-isomer resulting in approximately a 3-6-fold increase over the control value. These increases was paralleled by an increase in total carnitine acetyl transferase activity with a eudismic ratio of approximately 4. In addition, immunochemical detection by Western blotting analysis for both the microsomal cytochrome P450IVA1 isozyme and the peroxisomal bifunctional protein was in agreement with the above modulation of catalytic activities. These results are therefore not inconsistent with the hypothesis that cytochrome P450IVA1 induction and peroxisome proliferation are intimately linked. Whether the observed stereochemical selectivity resides in xenobiotic recognition or disposition still remains to be determined.
当雄性长 Evans 戴帽大鼠以 80 mg/kg 的剂量水平给予光学纯对映体形式和氯贝丁酯类似物[2-[4-(4-氯苯基)苄氧基]-2-苯基乙酸]的外消旋混合物 3 天时，观察到肝微粒体细胞色素 P450IVA1 和β-氧化螺旋体的过氧化物酶体酶的诱导。发现 R(-)-对映体比其相应的 S(+)-对映体更有效地诱导微粒体细胞色素 P450IVA1 及其相关的月桂酸 12-羟化酶活性。这种效力差异通过约为 3 的优值比（R/S 活性比）反映出来，而外消旋混合物的效力介于两种异构体之间。通过对氰化物不敏感的棕榈酰辅酶 A 氧化和过氧化物酶体β-氧化螺旋体的双功能蛋白的诱导判断，过氧化物酶体增殖现象观察到相同的对映体选择性。R(-)-异构体显示出最高的效力，导致比对照值增加约 3 - 6 倍。这些增加与总肉碱乙酰转移酶活性的增加平行，优值比约为 4。此外，通过蛋白质印迹分析对微粒体细胞色素 P450IVA1 同工酶和过氧化物酶体双功能蛋白进行免疫化学检测与上述催化活性的调节一致。因此，这些结果与细胞色素 P450IVA1 诱导和过氧化物酶体增殖密切相关的假设并不矛盾。观察到的立体化学选择性是存在于异源物识别还是处置中仍有待确定。
