Stereoselective metabolism of dibenz[a,h]acridine to bay-region diol epoxides by rat liver microsomes.
Stereoselective metabolism of dibenz[a,h]acridine to bay-region diol epoxides by rat liver microsomes.
复制标题
大鼠肝微粒体将二苯并[a,h]吖啶立体选择性代谢为湾区二醇环氧化物。
DOI：
10.1093/carcin/16.3.525
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发表时间：
1995
期刊：
影响因子：
4.7
通讯作者：
Sikka,HC
中科院分区：
文献类型：
--
作者：
Kumar,S;Singh,SK;Kole,PL;Elmarakby,S;Sikka,HC
The carcinogen dibenz[a,h]acridine (DB[a,h]ACR) is metabolized predominantly totrans-3,4-dihydroxy-3,4-dihydrodibenz[a,h]acridine (DB[a,h]ACR-3,4-diol) and the proximate carcinogentrans-10,11-dihydroxy-10,11-dihydrodibenz[a,h]acridine (DB[a,h]ACR-10,11-diol) [Stewardet al. (1987)Carcinogenesis, 8, 1043–1050]. In the present investigation, the stereoselectivity of rat liver enzymes in metabolism of DB[a,h]ACR to its 3,4-diol and 10,11-diol and of DB[a,h]ACR-10,11-diol enantiomers to their bay-region diol epoxides has been examined with liver microsomes from control and 3-methylcholanthrene-treated rats. Both microsomal preparations produced the major metabolites DB[a,h]ACR-3,4-diol and DB[a,h]ACR-10,11-diol containtaining predominantlyR,R-enantiomers with 38–54% optical purity. Metabolism of (−)-(10R,11R)- and (+)-(10S,11S)-enantiomers of DB[a,h]ACR-10,11-diol by liver microsomes from control rats produced predominantly bay-region diol epoxides (46–59% of total metabolites), whereas very little bay-region diol epoxides (14–17% of total metabolites) were produced by liver microsomes from 3-methylcholanthrene-treated rats. The bay-region diol epoxides produced in these studies consisted of predominantly DB[a,h]ACR-10,11-trans-diol epoxide diastereomer in which the benzylic hydroxyl group and epoxide oxygen are trans. However, (−)-DB[a,h]ACR-10R,11R-diol, a major metabolite of DB[a,h]ACR, was metabolized by liver microsomes from 3-methylcholanthrene-treated rats to (+)-[8R,9S,10S,11R]-DB[a,h]ACR-10,11-trans-diol epoxide, a diastereomer which displayed high mutagenic activity in V79 cells, in an amount which was 6.5-fold greater than that of the correspondingcis-diol epoxide diastereomer. The relative amounts oftrans-diol epoxide versuscis-diol epoxide in the mixture of bay-region diol epoxides produced from DB[a,h]ACR-10R,11R-diol and DB[a,h]ACR-10S,11R-diol with liver microsomes from control rats and from DB[a,h]ACR-10S,11S-diol with liver microsomes from 3-methylcholanthrene-treated rats were 1.7, 2.1 and 2.3 respectively.
