GLUCURONIDATION AND ISOMERIZATION OF ALL-TRANS-RETINOIC AND 13-CIS-RETINOIC ACID BY LIVER-MICROSOMES OF PHENOBARBITAL-TREATED OR 3-METHYLCHOLANTHRENE-TREATED RATS

Glucuronidation and isomerization of all-trans-retinoic acid (tr-RA) a nd 13-cis-retinoic acid (13-cis-RA) were investigated in an in vitro s ystem using liver microsomes of differently pretreated rats. In agreem ent with their thermodynamic stability, more retinoic acid was isomeri zed from the 13-cis form to the all-trans form than vice versa. Also s ome 9-cis-retinoic acid (9-cis-RA) could be found. Isomerization was r educed, but in contrast to glucuronidation was still important if boil ed microsomes were used. This supports the view that isomerization can proceed as a non-enzymatic process. 3-Methylcholanthrene (MC) pretrea tment of the rats increased the microsomal glucuronidation of 13-cis-R A 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 glucu ronidation by uninduced and phenobarbital-induced rat microsomes diffe red 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 ret inol to retinal and of retinyl methyl ether to retinol) this is a thir d step of retinoid metabolism, induced by pretreatment with MC. With h uman microsomes no more than traces of glucuronides were detected; als o, incubations with human microsomes resulted in a lower degree of iso merization than with rat microsomal fractions.