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  • Title: Characterization of dihydrodiol dehydrogenase in rat H-4IIe hepatoma cells.
    Author: Buller AL, Sharp RB, Penning TM.
    Journal: Cancer Res; 1989 Dec 15; 49(24 Pt 1):6976-80. PubMed ID: 2684404.
    Abstract:
    Dihydrodiol dehydrogenase (EC 1.3.1.20) catalyzes the NADP+-dependent oxidation of a variety of trans-dihydrodiol proximate carcinogens, a reaction that may suppress their carcinogenicity. Using benzenedihydrodiol [(+)-trans-1,2-dihydroxy-3,5-cyclohexadiene] as a substrate, this enzyme can be detected spectrophotometrically in rat H-4IIe hepatoma cells with a specific activity similar to that observed in rat liver cytosol. The hepatoma cell enzyme is potently inhibited by 6-medroxy-progesterone acetate (IC50 = 38 nM) and indomethacin (IC50 = 3.5 microM). These cells contain 3 alpha-hydroxysteroid dehydrogenase which is also sensitive to inhibition by the same two drugs. Chromatofocusing of hepatoma cell lysates indicates that both dihydrodiol dehydrogenase and 3 alpha-hydroxysteroid dehydrogenase activities coelute with a pI = 5.8. Western blot analysis of hepatoma cell lysates, using rabbit anti-rat 3 alpha-hydroxy-steroid/dihydrodiol dehydrogenase serum detects a single immunoreactive species with a Mr 34,000. Using this antiserum it was possible to immunotitrate both these enzyme activities in H-4IIe lysates. Exposure of confluent cells to either 10 microM benz[a]anthracene or 10 microM dexamethasone, which are known inducers in H-4IIe cells of aryl-hydrocarbon hydroxylase and tyrosine aminotransferase respectively, failed to elevate dihydrodiol dehydrogenase activity. The following agents also failed to induce dihydrodiol dehydrogenase activity: phenobarbital, ethoxyquin, phenolic anti-oxidants, testosterone, estradiol-17 beta, and growth hormone. Since the hepatoma cell enzyme has properties in common with the purified rat liver enzyme (which is identical to 3 alpha-hydroxysteroid dehydrogenase) including, Mr, pI, immunoreactivity, and sensitivity to drug inhibition, this cell line represents a useful system for studying the role of dihydrodiol dehydrogenase in the further metabolism of trans-dihydrodiols. Interestingly, the enzyme does not appear to be under the control of known inducers of phase I and phase II drug metabolizing enzymes.
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