Coexpression of Human Hepatic Uridine Diphosphate Glucuronosyltransferase Proteins: Implications for Ontogenetic Mechanisms and Isoform Coregulation.
Adolescent
Adult
Age Factors
Aged
Child
Child, Preschool
Female
Gene Expression Regulation
Glucuronides
/ metabolism
Glucuronosyltransferase
/ genetics
Humans
Infant
Infant, Newborn
Isoenzymes
/ genetics
Liver
/ enzymology
Male
Microsomes, Liver
/ enzymology
Middle Aged
Sex Characteristics
Young Adult
UGT coregulation
glucuronidation
ontogeny
protein-protein interaction
Journal
Journal of clinical pharmacology
ISSN: 1552-4604
Titre abrégé: J Clin Pharmacol
Pays: England
ID NLM: 0366372
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
10
10
2019
accepted:
02
12
2019
pubmed:
28
12
2019
medline:
22
6
2021
entrez:
28
12
2019
Statut:
ppublish
Résumé
Uridine diphosphate glucuronosyltransferases (UGTs) catalyze glucuronidation to facilitate systemic and local clearance of numerous chemicals and drugs. To investigate whether UGT expression is coregulated in human liver, we analyzed the protein expression of UGTs 1A1, 1A3, 1A4, 1A6, 1A9, 2B7, 3A1, and 3A2 using western blots from 164 healthy human liver samples, comparing expression with age and sex. UGT1A6 levels were significantly higher in children than adults, and UGT3A1 and 3A2 expression significantly increased with age from childhood to age >65 yearas. In children aged <18 years, UGT1A4/1A9 protein expression was significantly correlated, but not for adults aged >18 years. UGT1A3 expression was always significantly correlated with other UGT1A isoforms in all adults aged >18 years. In individuals aged ≥12 years, expression of UGT1A1/1A4, UGT1A1/1A6, UGT1A1/1A9, and UGT1A4/1A6 significantly correlated, which was not observed in children aged <12 years. In contrast, UGT1A4/2B7 showed significant correlation in children aged <12 years, but not in individuals aged ≥12 years, and this was observed in female but not male individuals. Expression of UGT1A6/1A9 and UGT3A1/3A2 correlated in the entire sample population, but UGT3As did not correlate with other UGTs. These correlations were sex dependent, as UGT1A3/1A1, UGT1A4/2B7 and UGT3A1/3A2 correlated more highly in male than female individuals, while UGT1A4/1A6 protein correlated more significantly in female than male individuals. This is the first report on the ontogeny of UGT3A isoforms, showing maximal expression in the elderly, and is the first demonstration that UGT isoforms commonly coexpress in vivo, in both age-dependent and sex-dependent manners.
Substances chimiques
Glucuronides
0
Isoenzymes
0
Glucuronosyltransferase
EC 2.4.1.17
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
722-733Informations de copyright
© 2019, The American College of Clinical Pharmacology.
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