All-trans-retinoic acid distribution and metabolism in vitamin A-marginal rats

Retinoids, including all-trans-retinoic acid (RA), are considered to have anti-inflammatory properties and are used therapeutically for diseases of the skin and certain cancers. However, few studies have addressed the effects of disease states on RA metabolism. The present study was conducted to better understand the effects of exogenous RA, both in the absence and presence of inflammation, on the distribution and metabolism of a dose of [H-3]RA. Female Sprague-Dawley rats fed a low vitamin A diet were pretreated with RA (po), a low dose of lipopolysaccharide (LPS, ip), or their combination. Twelve hours later, albumin-bound [H-3]RA was injected intravenously, and tissue organic- and aqueous-phase H-3 was determined after 10 and 30 min. In liver and plasma, H-3-labeled organic metabolites (e.g., 4-oxo- and 4-hydroxy-RA) were isolated by solid-phase extraction. LPS-induced inflammation significantly reduced plasma retinol by 47%, increased total H-3 in plasma at 10 min, and reduced total H-3 in liver at both times. In contrast, RA pretreatment did not affect plasma retinol, significantly increased total H-3 in plasma at both times, and did not affect liver total H-3. However, by 30 min, RA significantly increased [H-3] RA metabolism in plasma, liver, lung, and small intestine, as indicated by greater H-3-labeled aqueous-phase and H-3-labeled organic-phase metabolites. The results presented here demonstrate that, although LPS-induced inflammation affects the organ distribution of RA, the ability of RA to induce its own catabolism is maintained during inflammation. Thus we conclude that RA and LPS act independently to alter RA metabolism in vitamin A-marginal rats.