Characterization of β-Estradiol 3-Glucuronidation in Rat Brain

Abstract

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 (S 50 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.

The Active Glucuronide Metabolite of the Brain Protectant IMM-H004 with Poor Blood–Brain Barrier Permeability Demonstrates a High Partition in the Rat Brain via Multiple Mechanisms

“…Similarly, UGT1A7 mRNA expression has been observed in rat astrocytes [ 53 ], and glucuronidation activity toward IMM-H004 has been detected in the rat brain, suggesting the consistent glucuronidation of IMM-H004 in both rat and human brains. To further uncover the glucuronidation activity in different brain regions, Asai et al [ 54 ] compared the glucuronidation activity of β -estradiol, a UGT1A substrate, in microsomal proteins from various brain regions in rats. They observed that the hippocampus exhibited the highest activity, which was approximately twice that of the cerebrum.…”

Alterations of Cytochrome P450s and UDP-Glucuronosyltransferases in Brain Under Diseases and Their Clinical Significances

“…In human brain, UGT1A1 mRNA was detected (Kutsuno et al, 2015), but bilirubin glucuronidation was not (Ouzzine et al, 2014). A report showed that UGT1A1 might not be the main isoform catalyzing the glucuronidation in rat brain (Asai et al, 2017). Several reports indicated that brain mitochondria and microsomal CYPs also metabolized bilirubin (Hansen and Allen, 1997;Hansen, 2000).…”