New pathway for retinol metabolism in liver microsomes

Rat liver microsomes were discovered to actively oxidize retinol to polar metabolites, including 4-hydroxyretinol, in a system requiring oxygen and NADPH. Involvement of cytochrome P-450 was indicated by CO and SKF-525A inhibition and reconstitution of this system with purified forms of cytochrome P-450 (b and f). Addition of excess unlabeled retinoic acid did not decrease the specific activity of the products formed from labeled retinol, suggesting that retinoic acid is not involved as an intermediate step. Microsomal inducers (such as phenobarbital) strikingly enhanced the activity of the system, resulting in 5- to 10-fold increased rates of retinol degradation. Furthermore, microsomal substrates (such as benzphetamine) inhibited microsomal retinol metabolism. This new pathway of retinol metabolism in liver microsomes may explain, at least in part, vitamin A-drug interactions, including drug-induced hepatic depletion of vitamin A.