Rat liver UDP-glucuronosyltransferase. Identification of cDNAs encoding two enzymes which glucuronidate testosterone, dihydrotestosterone, and beta-estradiol.

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Abstract

The 1818-base pairs cDNA encoding a form of rat liver UDP-glucuronosyltransferase designated UDP-GTr-3 was sequenced and found to encode a protein of 530 amino acids (Mr = 60,522). Characteristic sequences include a signal peptide and a carboxyl-terminal transmembrane anchoring region. There were no potential asparagine-linked glycosylation sites. Transcription and translation of the cDNA in vitro showed that the encoded protein was synthesized as a precursor and was cleaved when dog pancreatic microsomes were present during translation. Cleaved UDPGTr-3 was intrinsically associated with the added membranes, whereas uncleaved polypeptide remained in the supernatant upon fractionation of the translation mixture. UDPGTr-3 and a related phenobarbital-inducible form of UDP-glucuronosyltransferase (designated UDPGTr-2) were both expressed in COS cells and their capacities to glucuronidate 13 commonly used substrates were analyzed. Whereas both enzymes glucuronidated the endogenous steroids testosterone, dihydrotestosterone, and beta-estradiol, only UDPGTr-2 was active towards the foreign chemical substrates, chloramphenicol, 4-hydroxybiphenyl, and 4-methylumbelliferone. Neither enzyme was active towards estrone, androsterone and substrates typical of 3-methylcholanthrene-inducible forms of UDP-glucuronosyltransferase. Steady-state levels of UDPGTr-3 and UDPGTr-2 mRNAs were highest in the liver and were barely detectable in kidney, lung, testis, and small intestinal mucosa. These data show that at least two forms of UDP-glucuronosyltransferase found predominantly in the liver have evolved to glucuronidate the same endogenous steroid substrates and that the phenobarbital-inducible form also has some activity towards foreign compounds.

Original languageEnglish
Pages (from-to)9744-9749
Number of pages6
JournalJournal of Biological Chemistry
Volume262
Issue number20
Publication statusPublished - 15 Jul 1987

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