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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 (K i 5K m 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 b-ionone ring system is likely to involve the microsomal ATRA 4-hydroxylase P450.