Mouse liver microsomal cholesterol epoxide hydrolase: a specific inhibition of its activity by 5,6 alpha-Imino-5 alpha-cholestan-3 alpha-OL

Abstract

A comparative study on mouse liver epoxide hydrolase activities has been done by using enzyme inhibitors in order to obtain evidence for the specificity of microsomal cholesterol epoxide hydrolase. 5,6 alpha-Imino-5 alpha-cholestan-3 beta-ol (IC) strongly inhibited the microsomal hydrolysis of cholesterol alpha-epoxide and the other delta 5-steroid alpha-epoxides (0.1 mM each) at concentrations less than 1 microM but affected neither microsomal nor cytosolic hydrolysis of any other epoxides of endogenous and exogenous compounds (0.1 mM each). On the other hand, 3,3,3-trichloropropene 1,2-oxide (TCPO) did not inhibited the microsomal hydrolysis of delta 5-steroid alpha-epoxides but strongly inhibited both microsomal and cytosolic hydrolysis of the other epoxides used. The only exceptions for the epoxy substrates that were not affected by both inhibitors were 5 alpha-cholest-2-ene alpha- and beta-epoxides. The inhibition by IC of the microsomal cholesterol alpha-epoxide hydrolysis was competitive, but no significant inhibition of the enzyme activity was observed by the typical microsomal xenobiotic substrates, hexadecene oxide and benzo[a]pyrene 4,5-oxide. These results strongly suggest that the microsomal enzyme hydrolyzing cholesterol alpha-epoxide differs from the microsomal hydrolase for epoxides of various xenobiotic olefins and arenes.