title: All-trans-retinoic acid 4-hydroxylation in human liver microsomes: in vitro modulation by therapeutic retinoids.
abstract: All-trans retinoic acid (ATRA) induces remission in patients with acute promyelocytic leukaemia. Other retinoids, including 9-cis- and 13-cis-retinoic acid (9-cis- and 13-cis-RA), are now being evaluated for their therapeutic potential. The elimination of ATRA is partially dependent on cytochrome P450 (P450)-mediated 4-hydroxylation, but the interaction of other retinoids with P450 has not yet been assessed. In the present study 9-cis- and 13-cis-RAs, as well as all-trans-retinol and three isomeric retinals were found to inhibit ATRA 4-hydroxylation in human hepatic microsomes, but the arotinoids acitretin and etretinate were not inhibitors 9-cis- and 13-cis-RA were competitive inhibitors of ATRA 4-hydroxylation (Ki:Km ratios 3.5 +/- 0.8 and 6.3 +/- 0.5, respectively) suggesting that these retinoids are alternate, but inferior, substrates for the P450 enzyme(s) that mediate the activity. The biotransformation of therapeutic retinoids containing the beta-ionone ring system is likely to involve the microsomal ATRA 4-hydroxylase P450.
authors.affiliation: Storr Liver Unit, Department of Medicine, University of Sydney, Westmead Hospital, New South Wales, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Nadin
authors.forename: M
authors.initials: M
authors.lastname: Murray
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D066298:In Vitro Techniques; D015474:Isotretinoin / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D012176:Retinoids / Q000494:pharmacology*; D014212:Tretinoin / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D012176:Retinoids; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D015474:Isotretinoin