Role of isozymes of rabbit microsomal cytochrome P-450 in the metabolism of retinoic acid, retinol, and retinal.
The metabolism of retinoic acid, retinol, and retinal has been investigated with eight purified rabbit cytochrome P-450 (P-450) isozymes, including the major forms in nasal and liver microsomes. Retinoids hydroxylated at the 4-position were found to be major metabolites with each of the isozymes examined. Only two of the isozymes, polycyclic aromatic hydrocarbon-inducible P-450 1A2 and antibiotic-inducible P-450 3A6, also catalyze the oxidation of retinal to retinoic acid, a reaction not previously attributed to P-450. P-450 1A2 showed high activities in both the 4-hydroxylation and aldehyde oxidation reactions. Phenobarbital-inducible P-450 2B4 also had high activity in the 4-hydroxylation reaction of retinoids, and cytochrome b5 was found to increase the activity of P-450 2B4 with each substrate but to increase the activity of P-450 1A2 only with retinoic acid. In microsomes, retinoic acid is converted in an NADPH-dependent manner to both 4-hydroxyretinoic acid and 4-oxoretinoic acid, but none of the isozymes investigated was found to convert the 4-hydroxy derivative to the 4-oxo derivative. Microsomes from animals treated with phenobarbital were more active than those from untreated animals in the 4-hydroxylation reaction and, consequently, showed an increase in the ratio of 4-hydroxy to 4-oxo derivatives produced. These results show that the individual forms of P-450 metabolize retinoic acid, retinol, and retinal to multiple products, and they indicate that the amounts formed may be dependent on the exposure of animals to various inducers of P-450.
Roberts
E S
ES
Department of Biological Chemistry, Medical School, University of Michigan, Ann Arbor 48109.
Vaz
A D
AD
Coon
M J
MJ
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D015786:Cytochromes b5 / Q000494:pharmacology; D006900:Hydroxylation / Q000187:drug effects; D007527:Isoenzymes / Q000502:physiology*; D007700:Kinetics; D008297:Male; D008861:Microsomes / Q000201:enzymology*; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009297:Nasal Mucosa / Q000201:enzymology; D011817:Rabbits; D012172:Retinaldehyde / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism*; D014801:Vitamin A / Q000378:metabolism*
D007527:Isoenzymes; D014801:Vitamin A; D014212:Tretinoin; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D012172:Retinaldehyde