Effect of caloric restriction on the stereoselective metabolism of 7-chlorobenz[a]anthracene by male B6C3F1 mouse liver microsomes

Abstract

The effect of caloric restriction (CR) on the stereoselective metabolism of 7-chlorobenz[a]-anthracene (7-CI-BA) by liver microsomes of 5-and 12-month-old male B6C3F1 mice was studied. Mice were fed ad libitum (AL), or starting at 14 weeks of age, received 60% of the calories consumed by control mice. After microsomal incubation, metabolites were extracted with ethyl acetate, purified by reversed-phase HPLC, and identified by analysis of their UV-visible and mass spectral data. The following ten metabolites were identified: 7-CI-BA trans-3,4-dihydrodiol, 7-CI-BA trans-5,6-dihydrodiol, 7-CI-BA trans-8,9-dihydrodiol, 7-CI-BA trans-10,11-dihydrodiol, 7-CI-BA 5,6-epoxide, and 4-, 5-, 6-, 8-, and 9-OH-7-CI-BA. Contrary to the metabolism of 7-Br-BA and 7-F-BA, the formation of 7-CI-BA trans-3,4-dihydrodiol in AL and CR microsomes were equivalent regardless of age. 7-CI-BA trans-8,9-dihydrodiol from liver microsomes of 5-month-old CR mice contained 95% of the R,R enantiomer and 5% of the S,S enantiomer, and thus had an optical purity of 90%. By comparison, the 7-CI-BA trans-8,9-dihydrodiol formed from liver microsomes of 5-month-old AL mice had an optical purity of 68%. On the other hand, the optical purity of 7-CI-BA trans-10,11-dihydrodiol formed from the AL microsomes was higher than that from CR microsomes. Thus, these results suggest that caloric restriction can alter the stereoselectivity of the cytochrome P-450 isozymes.