11β-Hydroxysteroid dehydrogenase type 1: tissue-specific expression and reductive metabolism of some anti-insect agent azole analogues of metyrapone

Abstract

The azole analogues of metyrapone are novel candidates for selective anti-insect agents that inhibit the synthesis of 20-hydroxyecdysone (20E), the moulting hormone of insects. Metyrapone, which is a model substrate for studying the reductive properties of oxidoreductases, is itself effectively reduced to the corresponding alcohol by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD 1). For this reason, the ability of 11β-HSD 1 to metabolize the metyrapone analogues as well was studied. In addition, the expression (by Western blots) and activity (reduction/oxidation of dehydrocorticosterone/corticosterone) of 11β-HSD 1 in different male and female mouse tissues were investigated. Xenobiotic carbonyl reductase activities in these tissues were assessed with metyrapone as a model substrate. The kinetic parameters of 11β-HSD 1 with metyrapone analogues as substrates were calculated after high-pressure liquid chromatography (HPLC) determination of the product alcohols. Our results indicate that the novel insecticides are extensively metabolized by mouse 11β-HSD 1. Moreover, the resulting alcohols are not only less toxic than the parent ketones but also have the potential, owing to the newly formed hydroxyl group, to be eliminated from the body by consecutive phase II reactions. Thus, the new metyrapone analogues may be potential anti-insect agents, safer for humans due to their reductive detoxification, mainly by the hepatic 11β-HSD 1, and selectively affecting insect development by inhibiting ecdysone 20-monooxygenase (E-20-M).