TY - JOUR
T1 - 4-Hydroxyretinoic acid, a novel substrate for human liver microsomal UDP-glucuronosyltransferase(s) and recombinant UGT2B7
AU - Samokyszyn, Victor M.
AU - Gall, Walter E.
AU - Zawada, Gregory
AU - Freyaldenhoven, Mary Ann
AU - Chen, Guangping
AU - Mackenzie, Peter I.
AU - Tephly, Thomas R.
AU - Radominska-Pandya, Anna
PY - 2000/3/10
Y1 - 2000/3/10
N2 - It is suggested that formation of more polar metabolites of all-trans- retinoic acid (atRA) via oxidative pathways limits its biological activity. In this report, we investigated the biotransformation of oxidized products of atRA via glucuronidation. For this purpose, we synthesized 4-hydroxy-RA (4- OH-RA) in radioactive and nonradioactive form, 4-hydroxy-retinyl acetate (4- OH-RAc), and 5,6-epoxy-RA, all of which are major products of atRA oxidation. Glucuronidation of these retinoids by human liver microsomes and human recombinant UDP-glucuronosyltransferases (UGTs) was characterized and compared with the glucuronidation of atRA. The human liver microsomes glucuronidated 4-OH-RA and 4-OH-RAc with 6- and 3-fold higher activity than atRA, respectively. Analysis of the glucuronidation products showed that the hydroxyl-linked glucuronides of 4-OH-RA and 4-OH-RAc were the major products, as opposed to the formation of the carboxyl-linked glucuronide with atRA, 4- oxo-RA, and 5,6-epoxy-RA. We have also determined that human recombinant UGT2B7 can glucuronidate atRA, 4-OH-RA, and 4-OH-RAc with activities similar to those found in human liver microsomes. We therefore postulate that this human isoenzyme, which is expressed in human liver, kidney, and intestine, plays a key role in the biological fate of atRA. We also propose that atRA induces its own oxidative metabolism via a cytochrome P450 (CYP26) and is further biotransformed into glucuronides via UGT-mediated pathways.
AB - It is suggested that formation of more polar metabolites of all-trans- retinoic acid (atRA) via oxidative pathways limits its biological activity. In this report, we investigated the biotransformation of oxidized products of atRA via glucuronidation. For this purpose, we synthesized 4-hydroxy-RA (4- OH-RA) in radioactive and nonradioactive form, 4-hydroxy-retinyl acetate (4- OH-RAc), and 5,6-epoxy-RA, all of which are major products of atRA oxidation. Glucuronidation of these retinoids by human liver microsomes and human recombinant UDP-glucuronosyltransferases (UGTs) was characterized and compared with the glucuronidation of atRA. The human liver microsomes glucuronidated 4-OH-RA and 4-OH-RAc with 6- and 3-fold higher activity than atRA, respectively. Analysis of the glucuronidation products showed that the hydroxyl-linked glucuronides of 4-OH-RA and 4-OH-RAc were the major products, as opposed to the formation of the carboxyl-linked glucuronide with atRA, 4- oxo-RA, and 5,6-epoxy-RA. We have also determined that human recombinant UGT2B7 can glucuronidate atRA, 4-OH-RA, and 4-OH-RAc with activities similar to those found in human liver microsomes. We therefore postulate that this human isoenzyme, which is expressed in human liver, kidney, and intestine, plays a key role in the biological fate of atRA. We also propose that atRA induces its own oxidative metabolism via a cytochrome P450 (CYP26) and is further biotransformed into glucuronides via UGT-mediated pathways.
UR - http://www.scopus.com/inward/record.url?scp=0034629096&partnerID=8YFLogxK
U2 - 10.1074/jbc.275.10.6908
DO - 10.1074/jbc.275.10.6908
M3 - Article
C2 - 10702251
AN - SCOPUS:0034629096
SN - 0021-9258
VL - 275
SP - 6908
EP - 6914
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 10
ER -