Expressed human UGT1.4 protein catalyzes the formation of quaternary ammonium-linked glucuronides.

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Green MD, Bishop WP, Tephly TR

Expressed human UGT1.4 protein catalyzes the formation of quaternary ammonium-linked glucuronides.

Drug Metab Dispos. 1995 Mar;23(3):299-302.

PubMed ID

7628292 [ View in PubMed

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Abstract

In humans, the metabolism of a number of tertiary amine-containing pharmacological agents to quaternary ammonium-linked glucuronides, catalyzed by UDP-glucuronosyltransferase (UGT), represents a unique and important metabolic pathway for these compounds. A full-length cDNA-encoding human UGT1.4 (the so-called "minor" human bilirubin UGT) was inserted into the expression vector pREP9 and transfected into human embryonic kidney 293 cells, and stable transfectants were obtained after geneticin selection. As expected, the expressed protein had low catalytic activity toward bilirubin. However, expressed human UGT1.4 protein exhibited glucuronidation activity toward tertiary amine substrates, such as imipramine, cyproheptadine, tripelennamine, and chlorpromazine, which form quaternary ammonium-linked glucuronides. Carcinogenic primary amines (beta-naphthylamine, benzidine, and 4-aminobiphenyl) also reacted with the expressed UGT1.4 protein at rates approximately 10-fold higher than the rates for quaternary ammonium glucuronide formation. Although a number of other UGT gene products are capable of catalyzing the glucuronidation of primary amine substrates, expressed human UGT1.4 protein is the only UGT isoform that has been shown to conjugate tertiary amine substrates, forming quaternary ammonium-linked glucuronides.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Cyproheptadine	UDP-glucuronosyltransferase 1-4	Protein	Humans	Unknown	Substrate	Details