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Drug Metab Pharmacokinet. 2002;17(4):348-56.

Molecular characterization of two monkey dihydrodiol dehydrogenases.

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1
Laboratory of Biochemistry, Gifu Pharmaceutical University, Mitahora-higashi, Japan.

Abstract

Japanese monkey liver contains multiple forms of dihydrodiol dehydrogenase with 3(20)alpha-hydroxysteroid dehydrogenase activity. Here we have purified the major and minor forms (DD1 and DD4) of the enzyme from Cynomolgus monkey liver, and isolated cDNA species for the two enzyme forms by reverse transcription-PCR. The cDNAs encoded proteins comprising of 323 amino acids, in which the sequence identity between DD1 and DD4 was 83%. The sequences deduced from the cDNAs for DD1 and DD4 perfectly matched the partial sequences of peptides derived from the respective enzymes. We also isolated the cDNAs for DD1 and DD4 of Japanese monkey liver, which had almost identical amino acid sequences with those of the respective enzymes of Cynomolgus monkey liver. The monkey DD1s and DD4s showed the highest sequence identity (94%) with AKR1C1 and AKR1C4, respectively, of four isoenzymes of human 3(20)alpha-hydroxysteroid dehydrogenase, which belongs to the aldo-keto reductase family. The substrate specificity and inhibitor sensitivity of the purified recombinant Cynomolgu monkey DD1 and Japanese monkey DD4 were also essentially identical to those of the recombinant AKR1C1 and AKR1C4, respectively, indicating that DD1 and DD4 are homologues of human AKR1C1 and AKR1C4, respectively. The mRNA for DD1 was detected only in liver, kidney, intestine and adrenal gland among Japanese monkey tissues, and that for DD4 was expressed in liver and kidney. These tissue distribution patterns differ from those of human AKR1C1 and AKR1C4, which are expressed ubiquitously and liver-specific, respectively. In addition, no mRNA for an enzyme corresponding to another isoenzyme (AKR1C2) of the human enzyme was detected in livers of the two monkey strains. The results suggest a difference in the metabolism of steroids and xenobiotics mediated by 3(20)alpha-hydroxysteroid dehydrogenase isoenzymes between monkeys and humans.

PMID:
15618685
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