Expression of UDP-Glucuronosyltransferase 1 (UGT1) and Glucuronidation Activity toward Endogenous Substances in Humanized UGT1 Mouse Brain

Although UDP-glucuronosyltransferases (UGTs) are important phase II drug-metabolizing enzymes, they are also involved in the metabolism of endogenous compounds. Certain substrates of UGTs, such as serotonin and estradiol, play important roles in the brain. However, the expression of UGTs in the huma...

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Published in:Drug metabolism and disposition 2015-07, Vol.43 (7), p.1071-1076
Main Authors: Kutsuno, Yuki, Hirashima, Rika, Sakamoto, Masaya, Ushikubo, Hiroko, Michimae, Hirofumi, Itoh, Tomoo, Tukey, Robert H, Fujiwara, Ryoichi
Format: Article
Language:English
Subjects:
Adult
Aging - metabolism
Animals
Brain Chemistry - genetics
Carbamazepine - pharmacology
Estradiol - metabolism
Female
Glucuronides - metabolism
Humans
Isoenzymes - biosynthesis
Isoenzymes - genetics
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microsomes - metabolism
Microsomes, Liver - drug effects
Microsomes, Liver - enzymology
Middle Aged
Monosaccharide Transport Proteins - genetics
Pregnenolone Carbonitrile - pharmacology
Serotonin - metabolism
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Summary:Although UDP-glucuronosyltransferases (UGTs) are important phase II drug-metabolizing enzymes, they are also involved in the metabolism of endogenous compounds. Certain substrates of UGTs, such as serotonin and estradiol, play important roles in the brain. However, the expression of UGTs in the human brain has not been fully clarified. Recently, humanized UGT1 mice (hUGT1 mice) in which the original Ugt1 locus was disrupted and replaced with the human UGT1 locus have been developed. In the present study, the expression pattern of UGT1As in brains from humans and hUGT1 mice was examined. We found that UGT1A1, 1A3, 1A6, and 1A10 were expressed in human brains. The expression pattern of UGT1As in hUGT1 mouse brains was similar to that in human brains. In addition, we examined the expression of UGT1A1 and 1A6 in the cerebellum, olfactory bulbs, midbrain, hippocampus, and cerebral cortex of hUGT1 mice. UGT1A1 in all brain regions and UGT1A6 in the cerebellum and cerebral cortex of 6-month-old hUGT1 mice were expressed at a significantly higher rate than those of 2-week-old hUGT1 mice. A difference in expression levels between brain regions was also observed. Brain microsomes exhibited glucuronidation activities toward estradiol and serotonin, with mean values of 0.13 and 5.17 pmol/min/mg, respectively. In conclusion, UGT1A1 and UGT1A6 might play an important role in function regulation of endogenous compounds in a region- and age-dependent manner. Humanized UGT1 mice might be useful to study the importance of brain UGTs in vivo.
ISSN:0090-9556
1521-009X
DOI:10.1124/dmd.115.063719