title: Glucuronidation and isomerization of all-trans- and 13-cis-retinoic acid by liver microsomes of phenobarbital- or 3-methylcholanthrene-treated rats.
abstract: Glucuronidation and isomerization of all-trans-retinoic acid (tr-RA) and 13-cis-retinoic acid (13-cis-RA) were investigated in an in vitro system using liver microsomes of differently pretreated rats. In agreement with their thermodynamic stability, more retinoic acid was isomerized from the 13-cis form to the all-trans form than vice versa. Also some 9-cis-retinoic acid (9-cis-RA) could be found. Isomerization was reduced, but in contrast to glucuronidation was still important if boiled microsomes were used. This supports the view that isomerization can proceed as a non-enzymatic process. 3-Methylcholanthrene (MC) pretreatment of the rats increased the microsomal glucuronidation of 13-cis-RA and tr-RA and the formation of 13-cis-retinoyl-beta-glucuronide was enhanced up to 7-fold by MC-induced rat microsomes. The rates of glucuronidation by uninduced and phenobarbital-induced rat microsomes differed only slightly. In addition to glucuronides of the applied retinoic acid isomers (13-cis-RA and tr-RA), 9-cis-RA and its glucuronide were found. Induction of retinoid glucuronidation by pretreatment with MC indicates that this metabolic reaction is catalysed by a MC-inducible UGT isozyme. After two recently described pathways (conversions of retinol to retinal and of retinyl methyl ether to retinol) this is a third step of retinoid metabolism, induced by pretreatment with MC. With human microsomes no more than traces of glucuronides were detected; also, incubations with human microsomes resulted in a lower degree of isomerization than with rat microsomal fractions.
authors.affiliation: Institut für Toxikologie und Embryopharmakologie, Freie Universität Berlin, Germany.
authors.forename: J O
authors.initials: JO
authors.lastname: Sass
authors.forename: A
authors.initials: A
authors.lastname: Forster
authors.forename: K W
authors.initials: KW
authors.lastname: Bock
authors.forename: H
authors.initials: H
authors.lastname: Nau
mesh_terms: D000818:Animals; D006801:Humans; D007536:Isomerism; D008297:Male; D008748:Methylcholanthrene; D008862:Microsomes, Liver / Q000378:metabolism*; D010634:Phenobarbital; D051381:Rats; D017208:Rats, Wistar; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: C026787:retinoyl glucuronide; D008748:Methylcholanthrene; D014212:Tretinoin; D010634:Phenobarbital