OXIDATIVE AND REDUCTIVE METABOLISM OF 9-CIS-RETINOIC ACID IN THE RAT - IDENTIFICATION OF 13,14-DIHYDRO-9-CIS-RETINOIC ACID AND ITS TAURINE CONJUGATE

g-cis-Retinoic acid (9-cis-RA), a hormone that binds and activates all known retinoid receptor subtypes, is structurally similar to all-tran s-retinoic acid and may share common metabolic fates. Both oral and in travenous doses of 9-cis-RA to rats led to hydroxylation and ketone fo rmation at carbon-4,9-Cis-RA also isomerized in vivo to 13-cis-retinoi c acid, 9-cis,13-cis-retinoic acid, and all-trans-retinoic acid. After administration of [11-H-3]S-cis-RA, the proportion of plasma radioact ivity that was volatile increased over time, which suggested that beta -oxidative chain-shortening of 9-cis-RA might occur. An equimolar mixt ure of [1-(CH3)-C-13-H-2]9-cis-RA and 9-cis-RA was administered to rat s for stable-isotope-labeled metabolite production, A chromatographic peak that had a lambda(max) = 290 nm vs. 348 nm for the parent compoun d, had a retention time similar to the parent, and yielded a 1:1 posit ive-ion isotope cluster at m/z 303/307 in its mass spectrum, NMR analy sis revealed 9-cis and 13,14-dihydro configurations, indicating that 9 -cis-RA can be metabolized in rat by reduction to 13,14-dihydro-9-cis- RA. An earlier-eluting HPLC peak that exhibited a lambda(max) at 290 n m, and a negative-ion-MS isotope cluster at mit 408/412 was observed d uring separations of rat liver extracts. LC/MS/MS analysis revealed pr oduct ions for this peak diagnostic for carboxylic acid taurine conjug ates. In rats, reduction of 9-cis-RA to 13,14-dihydro-9-cis-RA may rep resent an initial step leading to beta-oxidation, although available d ata demonstrate it is conjugated with taurine to form a novel metaboli te.