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Abstract
1. Rat liver microsomes converted d-limonene to the 1,2-epoxide (1-methyl-4-(1′-methylethenyl)-7-oxabicyclo[4,1,0]heptane), the 8,9-epoxide (1-methyl-4-(1′-methyl-1′,2′-epoxyethyl)cyclohex-1-ene), and the 8,9-glycol (2-(4′-methylcyclohex-3′-en-1′-yl) propane-1,2-diol) in the presence of NADPH. The 8,9-glycol was formed in the highest yield, the 1,2-epoxide in next highest yield, and the 8,9-epoxide was formed in low yield.
2. The absence of the 1,2-glycol (1-methyl-4-(1′-methylethenyl)cyclohexene-1,2-diol) as a microsomal metabolite of d-limonene was attributed to the very low rate of microsomal hydrolysis of the 1,2-epoxide: about 1% of the rate for the 8,9-epoxide.
3. The epoxide hydrolase inhibitor, 3,3,3-trichloropropene 1,2-oxide, completely inhibited microsomal hydrolysis of the 8,9-epoxide formed from d-limonene, and resulted in its accumulation in the reaction medium without yielding any detectable amount of the 8,9-glycol.
4. From comparison with a study on the microsomal metabolism of 4-vinylcyclohex-1 -ene, the biological selectivity in the microsomal oxidation of the d-limonene double bonds was attributed to a steric hindrance effect of the C1-methyl group.
5. In the less hindered 4-vinylcyclohex-1-ene molecule, microsomal epoxidation occurred preferentially at the C1-double bond, a site readily epoxidizable by chemical oxidants. Hydrolysis of 4-vinylcyclohex-1-ene epoxides by microsomal epoxide hydrolase also occurred at higher rate with the less alkyl-substituted vinyl epoxide moiety.
6. d-Limonene, 4-vinylcyclohex-1-ene, and their epoxides were all non-mutagenic toward Salmonella typhimurium TA 98, TA 100, TA 1535, TA 1537, and TA 1538 in the presence and in the absence of a PCB-induced rat liver 9000 g supernatant fraction fortified with a NADPH-generating system.