Retinoids biotransformation

It should be emphasized that investigations of embryonic enzymatic catalysis of the four retinoid biotransforming reactions (2ill-trans/9-cis isomerization, retinol and retinal dehydrogenation, glucuronidation and monooxygenation) have been numerous [6,7,10-13,15,18-22, 77-85]. 

CYP1B1 is also expressed in the fetus in multiple tissues, particularly in thymus, spleen, kidney, and adrenal. A null CYP1B1 phenotype in humans has been associated with appearance of primary congenital glaucoma. Consistent with an important endogenous role for this enzyme in development of the eye, CYP1B1—which, in addition to biotransformation of xenobiotics, is also capable of metabolizing retinoid and sex steroids—is expressed in embryonic ocular tissues. 

The paradigm emerging is that of a cascade (a series of biochemical steps using secondary, tertiary, or more messenger molecules, each successive step amplifying those of the preceding step). After retinoid absorption from the gut, biotransformation in the liver, transport through the blood and across the... 

Little is known of the mechanisms by which environmental chemicals deplete retinoid stores. In many field studies there is evidence of increased activity of phase I and II biotransformation enzymes, and both are thought to directly metabolize retinoids. P450 enzymes also produce oxyradicals causing oxidative stress34,72,73, which may lead to retinoid use as antioxidants. There was evidence of oxidative stress and retinoid depletion in lake trout inhabiting an area contaminated with iron-ore mine tailings80, yet it is unlikely that this exposure would be associated with induction of phase I or II biotransformation enzymes. 

Kochhar, D.M. Penner, J.D. Minutella, L.M. Biotransformation of etretinate and developmental toxicity of etretin and other aromatic retinoids in teratogenesis bioassays. Drug Metab.Dispos., 1989, 17, 618-624... 

CYP26 expression in normal human tracheobronchial epithelial cells was compared with that in human lung carcinoma cell lines (Kim et al. 2000). CYP26 mRNA could be induced by the retinoic acid receptor-selective retinoid 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-benzoic acid but not by the retinoid X receptor-selective retinoid SRI 1217 or the anti-activator-protein 1-selective retinoid SRI 1302. Retinoic acid receptor a-, P, and y-selective retinoids were able to induce CYP26 this induction was inhibited by the retinoic acid receptora-selective antagonist Ro41-5253. The induction of CYP26 correlated with increased biotransformation of retinoic acid into 18-hydroxy-, 4-OXO-, and 4-hydroxy-retinoic acid. 

S Hashimoto, M Mizobuchi, T Kuroda, H Okabe, K Mizojiri, S Takahashi, J Ki-kuchi, Y Terui. Biotransformation of a new synthetic retinoid, 4-[5,6,7,8-tetrahy-dro-5,5,8,8-tetramethyl-2-naphthyl)carbamoyl]benzoic acid (Am-80), in the rat. Structure elucidation of the metabolites by mass and NMR spectrometry. Xenobiot-ica 24 1177-1193, 1994. 

Ross AC, Zolfaghari R, and Weisz J (2001) Vitamin A recent advances in the biotransformation, transport, and metabolism of retinoids. Current Opinionsin Gastroenterology 17 184-192. 

---