β-Estradiol is conjugated by uridine 5'-diphosphate-glucuronosyltransferase (UGT) 1A to 3-glucuronide in the human liver. UGT1A has been found in the brain; therefore, UGT1A may be involved in β-estradiol 3-glucuronidation in the brain. In the present study, we aimed to characterize the β-estradiol 3-glucuronidation reaction in the rat brain. β-Estradiol 3-glucuronidation was detected in eight rat brain regions (cerebellum, frontal cortex, parietal cortex, piriform cortex, hippocampus, medulla oblongata, striatum, and thalamus). β-Estradiol 3-glucuronidation in the cerebellum was fitted to the Hill equation (S50=8.0 µM, n=1.1). In inhibition experiments, β-estradiol 3-glucuronidation was inhibited to 73.6% in the cerebellum by 50 µM bilirubin, whereas it was reduced to 20.5% with 5 µM bilirubin in the liver. Unlike in the liver, Ugt1a1 may not be the main isoform catalyzing this glucuronidation in the brain. Serotonin and acetaminophen at 10 mM inhibited glucuronidation to 1.17 and 25.5%, respectively, in the cerebellum. In induction experiments, the administration of β-naphthoflavone, carbamazepine, and phenobarbital did not increase β-estradiol 3-glucuronidation in the brain except for phenobarbital in the striatum. In addition, β-estradiol 3-glucuronidation was not correlated with serotonin or acetaminophen glucuronidation in the brain, suggesting that Ugt1a6 and Ugt1a7 are not major isoforms of β-estradiol 3-glucuronidation in the rat brain. In the present study, although we were unable to identify the isoform responsible for β-estradiol 3-glucuronidation, we confirmed that β-estradiol could be metabolized to glucuronide in the brain under a different metabolic profile from that in the liver.
Keywords: brain; enzyme kinetics; induction; inhibition; uridine 5′-diphosphate-glucuronosyltransferase; β-estradiol.