Lubet R A, Dragnev K H, Chauhan D P, Nims R W, Diwan B A, Ward J M, Jones C R, Rice J M, Miller M S
Laboratory of Comparative Carcinogenesis, NCI-Frederick Cancer Research and Development Center, MD 21702.
Biochem Pharmacol. 1992 Mar 3;43(5):1067-78. doi: 10.1016/0006-2952(92)90614-o.
The effects of a number of phenobarbital-type inducers on selected drug-metabolizing enzymes in male F344/NCr rats were determined by measuring specific catalytic activities and/or by measuring the levels of RNA which hybridize with specific probes for the corresponding genes. The effects on hepatic CYP2B1 were assessed by measuring the levels of CYP2B1-specific RNA and benzyloxyresorufin O-dealkylase and testosterone 16 beta-hydroxylase activities. Levels of CYP3A were monitored by measuring the rate of hydroxylation of testosterone at the 6 beta-position. Microsomal epoxide hydrolase activity was determined by measurement of cellular RNA specific for this form and by assaying the hydrolysis of benzo[a]pyrene-4,5-oxide. UDP-glucuronyltransferase activity was assayed by measuring the glucuronidation of 3-hydroxybenz[a]anthracene. Levels of glutathione S-transferase Ya/Yc were measured by quantifying total cellular RNA coding for the proteins. When male F344/NCr rats were administered various doses of phenobarbital or dichlorodiphenyltrichloroethane (DDT), strong correlations between the induction of CYP2B1 and the induction of epoxide hydrolase or UDP-glucuronyltransferase activities were observed. Treatment of rats with barbiturates, hydantoins, halogenated pesticides such as DDT or alpha-hexachlorocyclohexane, 2,4,5,2',4',5'-hexachlorobiphenyl, CYP2B1 inhibitors such as clotrimazole or clonazepam, or such structurally-diverse compounds as 2-hexanone or diallyl sulfide resulted in induction of CYP2B1-mediated enzyme activity and induction of certain other forms of cytochrome P450, microsomal epoxide hydrolase, at least one form of UDP-glucuronyltransferase, and multiple forms of glutathione S-transferase. This suggests that, as a class, compounds which induce CYP2B1 also induce a coordinate hepatic pleiotropic response which includes induction of these other phase I and phase II drug-metabolizing enzymes.
通过测量特定催化活性和/或通过测量与相应基因的特异性探针杂交的RNA水平，确定了多种苯巴比妥类诱导剂对雄性F344/NCr大鼠中选定的药物代谢酶的影响。通过测量CYP2B1特异性RNA水平、苄氧基试卤灵O-脱烷基酶和睾酮16β-羟化酶活性，评估对肝脏CYP2B1的影响。通过测量睾酮在6β位的羟化速率来监测CYP3A水平。微粒体环氧化物水解酶活性通过测量该形式的细胞特异性RNA和通过测定苯并[a]芘-4,5-氧化物的水解来确定。UDP-葡萄糖醛酸转移酶活性通过测量3-羟基苯并[a]蒽的葡萄糖醛酸化来测定。通过定量编码这些蛋白质的总细胞RNA来测量谷胱甘肽S-转移酶Ya/Yc水平。当给雄性F344/NCr大鼠施用不同剂量的苯巴比妥或二氯二苯三氯乙烷（DDT）时，观察到CYP2B1的诱导与环氧化物水解酶或UDP-葡萄糖醛酸转移酶活性的诱导之间存在强相关性。用巴比妥类、乙内酰脲类、卤代农药如DDT或α-六氯环己烷、2,4,5,2',4',5'-六氯联苯、CYP2B1抑制剂如克霉唑或氯硝西泮，或结构多样的化合物如2-己酮或二烯丙基硫醚处理大鼠，导致CYP2B1介导的酶活性诱导以及某些其他形式的细胞色素P450、微粒体环氧化物水解酶、至少一种形式的UDP-葡萄糖醛酸转移酶和多种形式的谷胱甘肽S-转移酶的诱导。这表明，作为一类，诱导CYP2B1的化合物也诱导一种协调性的肝脏多效性反应，其中包括这些其他I相和II相药物代谢酶的诱导。
