Retinoic Acid Metabolism and Mechanism of Action: A Review

Abstract

Retinoids are vitamin A (retinol) derivatives essential for normal embryo development and epithelial differentiation. These compounds are also involved in chemoprevention and differentiation therapy of some cancers, with particularly impressive results in the management of acute promyelocytic leukemia (APL). Although highly effective in APL therapy, resistance to retinoic acid (RA) develops rapidly. The causes of this resistance are not completely understood and the following factors have been involved: increased metabolism, increased expression of RA binding proteins, P-glycoprotein expression, and mutations in the ligand binding domain of RARalpha. RA exerts its molecular actions mainly through RAR and RXR nuclear receptors. In addition to the nuclear receptor based mechanism of RA action, covalent binding of RA to cell macromolecules has been reported. RA derives from retinol by oxidation through retinol and retinal dehydrogenases, and several cytochrome p450s (CYPs). RA is thereafter oxidized to several metabolites by a panel of CYPs that differs for the different RA isomers. Phase II metabolism, mainly glucuronidation, is also observed. The role RA metabolism plays in the expression of its biological actions is not completely understood: in several systems, metabolism decreases RA activity, whereas in other systems metabolism appears involved in its action. In addition, several RA metabolites have shown activity and cannot be classified as only catabolites. Therapy of cancer with retinoids is still in its infancy, but the use of new analogues with improved pharmacological properties, along with combination with other drugs, could undoubtedly improve the management of several cancers in the future.

Identification of Retinoic Acid Receptor Agonists in Sewage Treatment Plants

“…Previous studies have reported that all-trans-4-oxo-RA and 13-cis-4-oxo-RA widely exist in human and animal serum (36,37) and can be eliminated from the body through urinary excretion (38). In another study, Li et al also detected the glucuronide conjugate of all-trans-4-oxo-RA and 13-cis-4-oxo-RA in urine of rats that had been fed with all-trans-RA, 9-cis-RA, and 13-cis-RA previously (39).…”

Retinol-binding protein 4 is associated with components of the metabolic syndrome, but not with insulin resistance, in men with type 2 diabetes or coronary artery disease

“…Consistent with the above, we found an independent association between RPB4 levels and hepatic lipase activity in patients with type 2 diabetes and in those with CAD. RBP4 is a transporter protein for retinol that serves as a precursor for the synthesis of ligands of the retinoid X receptor and retinoic acid receptor nuclear hormone receptors [19]. In previous studies, retinoids increased the hepatic production of VLDL [20] and elevated the levels of apolipoprotein (apo) C-III [21], a hepatic protein that delays (1) the catabolism of VLDL particles by inhibiting their binding to the endothelial surface and (2) lipolysis by lipoprotein lipase [22].…”

Dietary determinants of subclinical inflammation, dyslipidemia and components of the metabolic syndrome in overweight children: a review

“…Retinoids can stimulate phosphoenolpyruvate carboxykinase expression in the liver and hepatic gluconeogenesis. In addition, retinol is a precursor for the synthesis of ligands of the retinoic acid receptor (RAR) and retinoid X receptor (RXR) nuclear receptors; 125,126 these are partners of the peroxisome proliferator-activated receptor family that regulate genes central to fatty acid metabolism. 127 RBP4 could thus be linked to insulin resistance through impaired fatty acid metabolism, 128 and expression of several retinoidresponsive genesFRAR 2, stearoyl-CoA desaturase-1 and acetyl CoA carboxylaseFis increased in the muscle of RBP4-Tg mice.…”