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

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 (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.

Oxidation of retinoic acids in hepatic microsomes of wild bullfrogs Lithobates catesbeianus environmentally-exposed to a gradient of agricultural contamination

“…As these two synthetic antifungal compounds are known to inhibit CYP450 activity, one may conclude that the activity measured in our assay is influenced, at least in part, by enzymes of the CYP450 family. Nadin and Murray (1996) demonstrated a competitive inhibition of 9cisRA and 13cisRA on the atRA hydroxylation, suggesting that the three RA isomers are hydroxylated by a common P450 system (Qian et al 2010). Cytochromes responsible for the 13cisRA hydroxylation in the bullfrog's liver are still to be determined.…”