Androgen induction of alcohol dehydrogenase in mouse kidney. Studies with a cDNA probe confirmed by nucleotide sequence analysis

Jd, Ceci; Lawther, Robert P.; Duester, Gregg; Hatfield, G. Wesley; Smith, Martin A.; Mp, O'Malley; Mr, Felder

doi:10.1016/0378-1119(86)90101-0

Cited by 31 publications

(19 citation statements)

References 25 publications

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“…(23,24). We screened a mouse 129/SvJ genomic library (Stratagene, La Jolla, California) using a mouse Adh1 cDNA (25) and isolated a clone containing the region spanning from exon 4 to the 3Ј-flanking region. A ScaI-EcoRV DNA fragment of 2.2 kb containing the 3Ј-flanking region of Adh1 was blunt end cloned into the XbaI site of plasmid pTK-neo, which lies between the PGK-neo and PGK-tk gene cassettes (26).…”

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Metabolic Deficiencies in Alcohol Dehydrogenase Adh1,Adh3, and Adh4 Null Mutant Mice

Deltour

Foglio

Duester

1999

Journal of Biological Chemistry

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166

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Targeting of mouse alcohol dehydrogenase genes Adh1, Adh3, and Adh4 resulted in null mutant mice that all developed and reproduced apparently normally but differed markedly in clearance of ethanol and formaldehyde plus metabolism of retinol to the signaling molecule retinoic acid. Following administration of an intoxicating dose of ethanol, Adh1 ؊/؊ mice, and to a lesser extent Adh4 ؊/؊ mice, but not Adh3 ؊/؊ mice, displayed significant reductions in blood ethanol clearance. Ethanol-induced sleep was significantly longer only in Adh1 ؊/؊ mice. The incidence of embryonic resorption following ethanol administration was increased 3-fold in Adh1 ؊/؊ mice and 1.5-fold in Adh4 ؊/؊ mice but was unchanged in Adh3 ؊/؊ mice. Formaldehyde toxicity studies revealed that only Adh3 ؊/؊ mice had a significantly reduced LD 50 value. Retinoic acid production following retinol administration was reduced 4.8-fold in Adh1 ؊/؊ mice and 8.5-fold in Adh4 ؊/؊ mice. Thus, Adh1 and Adh4 demonstrate overlapping functions in ethanol and retinol metabolism in vivo, whereas Adh3 plays no role with these substrates but instead functions in formaldehyde metabolism. Redundant roles for Adh1 and Adh4 in retinoic acid production may explain the apparent normal development of mutant mice. The alcohol dehydrogenase (ADH)1 family consists of numerous enzymes able to catalyze the reversible oxidation of a wide variety of xenobiotic and endogenous alcohols to the corresponding aldehydes (1). Several distinct classes of vertebrate ADH have been described, all of which are cytosolic and zincdependent but differ in substrate specificities and gene expression patterns (2, 3). Three forms that are highly conserved in mammals and other vertebrates are class I ADH (ADH1), class III ADH (ADH3), and class IV ADH (ADH4); see Ref. 1 for ADH nomenclature. Biochemical studies indicate that these three ADHs are able to utilize a wide variety of alcohol and aldehyde substrates in vitro ranging from ethanol to formaldehyde to retinol. However, the precise functions of these enzymes are not yet well established. In humans, ADH4 demonstrates higher retinol dehydrogenase activity than ADH1 with ADH1 having higher ethanol dehydrogenase activity than ADH4 and ADH3 having insignificant retinol or ethanol dehydrogenase activity (4 -6). Instead, ADH3 has glutathione-dependent formaldehyde dehydrogenase activity, i.e. upon reaction of formaldehyde with glutathione to produce S-hydroxymethylglutathione, ADH3 oxidizes the hydroxymethyl group to a formyl group to produce S-formylglutathione, which is then the substrate for a hydrolase that regenerates glutathione and produces formate (7).The potential role of ADH1 and ADH4 in retinol metabolism is particularly interesting because this pathway produces retinoic acid, which is a physiological ligand controlling numerous retinoic acid receptor signaling pathways (8). Also, the potential dual roles of ADH1 and ADH4 as ethanol and retinol dehydrogenases have led us to propose that alcohol abuse may lead to ethanol inhibition of ADH-c...

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confidence: 99%

Metabolic Deficiencies in Alcohol Dehydrogenase Adh1,Adh3, and Adh4 Null Mutant Mice

Deltour

Foglio

Duester

1999

Journal of Biological Chemistry

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166

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“…1. 1) (1). Although the exact physiological role of ADH is uncertain, it catalyzes the oxidation or the reduction of several physiological endogeneous steroidal and nonsteroidal substrates , in addition to ethanol (2)(3)(4)(5) …”

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Effect of Sex Hormones on Rat Liver Cytosolic Alcohol Dehydrogenase Activity.

Harada

Tachiyashiki

Imaizumi

1998

Journal of Nutritional Science and Vitaminology, J Nutr Sci Vit

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“…ADH-A2, ADH-B2, and ADH-C2 are encoded by the Adh-i, Adh-2, and Adh-3 genes, respectively. Adh-J is subject to both developmental and hormonal control (10,14,15). Developmental variation in liver ADH-A2 expression among inbred strains is due to variation at a single locus designated Adh-it, which acts by controlling the rate of ADH-A2 synthesis (10).…”

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“…Developmental variation in liver ADH-A2 expression among inbred strains is due to variation at a single locus designated Adh-it, which acts by controlling the rate of ADH-A2 synthesis (10). In the kidney, androgen increases the rate of ADH-A2 synthesis and ADH-1 mRNA concentration (14,16). Mechanistically, the response involves an increase in the relative rate oftranscription as well as changes in posttranscriptional control (16).…”

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“…RNA preparations were routinely analyzed for quality by agarose gel electrophoresis as well as absorbance ratios at 260 and 280 nm. Tissue levels of Adh-l-encoded mRNA were estimated by hybridization to slot blots as described (14) except that radioactivity was detected by scintillation counting. Different amounts of total RNA were spotted, depending on the relative concentration of ADH-1 mRNA in that tissue, to ensure that the measurements were in the range of linearity.…”

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Tissue-specific genetic variation in the level of mouse alcohol dehydrogenase is controlled transcriptionally in kidney and posttranscriptionally in liver.

Tussey

Felder²

1989

Proc. Natl. Acad. Sci. U.S.A.

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Tissue-specific genetic variation in expression of the alcohol dehydrogenase, encoded by the Adh-i gene, is found between C57BL/6J (B6) mice and B6.S congenic mice. B6.S mice contain a variant Adh-1 allele derived from a wild Danish strain in a B6 genetic background. B6 mice have nearly twice the alcohol dehydrogenase activity in liver but less than half the activity in kidney as B6.S mice. These tissue-specific genetic changes in alcohol dehydrogenase expression are manifest at the level of Adh-i-encoded mRNA. The regulatory site(s) involved act cis in both kidney and liver. These strains also differ in the extent to which androgen induces mRNA encoded by kidney Adh-1, with androgen increasing these levels 17-fold and 7.4-fold in the B6 and B6.S kidney, respectively. To identify the regulatory mechanism(s) underlying this strain variation in Adh-l expression, estimates were obtained for the relative rate ofAdh-1 transcription in the B6 and B6.S kidney, liver, and androgen-induced kidney. For both uninduced and induced kidney, a difference in the transcription rate alone accounts for the strain difference in mRNA concentration. In contrast, because the Adh-l transcription rate in liver does not differ significantly between B6 and B6.S mice, strain-specific variation in posttranrscriptional regulation must be operative.Taken together these results indicate that the variation in Adh-1 expression between B6 and B6.S mice results from changes in both transcriptional and posttranscriptional control, and these controls are differentially operative in kidney and liver.

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Androgen induction of alcohol dehydrogenase in mouse kidney. Studies with a cDNA probe confirmed by nucleotide sequence analysis

Cited by 31 publications

References 25 publications

Metabolic Deficiencies in Alcohol Dehydrogenase Adh1,Adh3, and Adh4 Null Mutant Mice

Metabolic Deficiencies in Alcohol Dehydrogenase Adh1,Adh3, and Adh4 Null Mutant Mice

Effect of Sex Hormones on Rat Liver Cytosolic Alcohol Dehydrogenase Activity.

Tissue-specific genetic variation in the level of mouse alcohol dehydrogenase is controlled transcriptionally in kidney and posttranscriptionally in liver.

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