All‐trans‐retinoic acid 4‐hydroxylation in human liver microsomes: in vitro modulation by therapeuticretinoids

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:K_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 β‐ionone ring system is likely to involve the microsomal ATRA 4‐hydroxylase P450.

DOI: 10.1046/j.1365-2125.1996.34919.x

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