Abstract
All trans retinoic acid (RA), derived from the oxidative metabolism of dietary retinol (vitamin A) and β carotene, contributes to the growth and differentiation of mammalian epithelial tissues. RA is rapidly cleared from the plasma and sudenly metabolized in tissues. The increase of its biological potency through inhibition of its oxidative metabolism is consistent with this.This research is part of a study to develop novel compounds as inhibitors of retinoic acid metabolism that could have potential value as anticancer agent. The investigation was done to compare the in vitro metabolism of [3H]RA by hepatic m icrosomes from several common laboratory animal species. Also, the ability of ketaconazole to inhibit RA metabolism was examined. The species studied were male rat, male New Zealand white rabbit, male albino mouse, male Syrian hamster, male Dunkin hartley guinea pig and male nude mouse. The results revealed that km and Vmax were species dependent. Among the animals, rat liver appeared to be the most active in metabolizing RA. Inhibition of RA metbolism by ketoconazole (100 µM) was very similar in the hepatic microsomes of all the species examine. Overall the results indicate that male rat hepatic microsomes represent a useful enzyme source for screening novel compounds as inhibitors of RA metabolism.
Highlights
All trans retinoic acid (RA), derived from the oxidative metabolism of dietary retinol and 0 carotene, contributes to the growth and differentiation of mammalian epithelial tissues
IN VITROHEPATIC METABOLISM OF RA BY DIFFERENT SPECIES: Results from the RA metabolism assays were analyzed by Lineweaver Burk plots (Figure:2)
The results showed that ketoconazole inhibited the metabolism of RA in all the microsomes samples examined
Summary
All trans retinoic acid (RA), derived from the oxidative metabolism of dietary retinol (vitamin A) and 0 carotene, contributes to the growth and differentiation of mammalian epithelial tissues. All- trans retinoic acid (RA) is the principal endogenous retinoid and has been used successfully in differentiating therapy of acute promyelocytic leukemia (1,2) It is currently being investigated for efficacy in the treatment and prevention of various types of cancer. In previous work the investigation was done to elucidate the rate of RA metabolism at different tissue sites of male rat (liver, kidney, intestinal mucosa, lung, skin and brain) and its inhibition by P-450 3A4 ligand ketoconazole (13). The results of those experiments revealed that RA metabolism occurred in all organs of the male rat selected for study, with liver being the most active. The species studied were male and female rat, male New Zealand white rabbit, male albino mouse, male Syrian hamster, male Dunkin hartley guinea pig and male nude mouse
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