Mouse alcohol dehydrogenase isozymes: Products of closely localized duplicated genes exhibiting divergent kinetic properties

Holmes, Roger S.; Albanese, R.; Whitehead, Faye D.; Duley, John A.

doi:10.1002/jez.1402170202

Cited by 37 publications

(12 citation statements)

References 21 publications

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“…Production of Adh1/Adh4 homozygous double mutants will serve to further decipher the role of ADHs in physiological retinol utilization, but this will be difficult because these genes have been mapped to the same general region of mouse chromosome 3 (46). We attempted to generate such double mutants by mating Adh1 and Adh4 null mutant mice and looking for crossover events in mice heterozygous for both Adh1 and Adh4 mutations.…”

Section: Resultsmentioning

confidence: 99%

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

Deltour

Foglio

Duester

1999

Journal of Biological Chemistry

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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Section: Resultsmentioning

confidence: 99%

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

Deltour

Foglio

Duester

1999

Journal of Biological Chemistry

166

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“…ADH-A2 and ADH-C2 are the products of two closely linked murine gene loci, Adh-1 and Adh-2, respectively (Holmes et al, 1981). Only one of these isoenzymes, ADH-A2, is a class I ADH (Ceci et al, 1987;Zhang et al, 1987).…”

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confidence: 99%

Stage and tissue‐specific expression of the alcohol dehydrogenase 1 (Adh‐1) gene during mouse development

Vonesch

Nakshatri

Philippe

et al. 1994

Developmental Dynamics

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The Adh-1 gene product, ADH-A2, the only known murine class I alcohol dehydrogenase, is able to oxidize retinol (vitamin A) into retinaldehyde, the first enzymatic step in the conversion of retinol into its biologically active metabolite retinoic acid. We have investigated the developmental expression pattern of Adh-1 transcripts by in situ hybridization. Transcripts were first detected by embryonic day 10.5 in the mesonephros mesenchyme. During the following gestational days, Adh-1 transcripts were detected in several mesenchymal areas, such as nasal, laterocervical, and genital regions. Adh-1 transcripts were also detected in a small ectodermal domain at the anterior margins of both forelimbs and hindlimbs. During late fetal development, Adh-1 transcripts were found essentially in the epidermis and in a number of tissues which continue to express the gene after birth, such as liver, kidney, gut epithelium, adrenal cortex, testis interstitium, and ovarian stroma. In contrast, a strong expression of Adh-1 was found in the mesenchyme of developing lungs, but not in the adult organ. This highly regulated expression of Adh-1 is discussed with respect to the local synthesis of retinoic acid during development. Although the promoter of the human counterpart of Adh-1 contains a retinoic acid response element (Duester et al. 119913 Mol. Cell. Biol. 11:1638-1646), we report that this element is not conserved in the murine gene. Consistently, Adh-1 promoter-containing reporter constructs were not retinoic acid-inducible in cotransfections assays with RARs and/or RXRs, suggesting that retinoic acid regulation of Adh-1 differs from that of the human gene.

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“…While androgen induces ADH-1 mRNA levels 17-fold in the B6 kidney, ADH-1 mRNA concentration increases only 7.4- Adh-Jalb female mice were identified (10,18) and mated to B6 males. After 10 generations of backcrossing, heterozygous animals were mated to obtain the B6.S congenic line that is homozygous for the Adh-lb allele.…”

mentioning

confidence: 99%

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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Mouse alcohol dehydrogenase isozymes: Products of closely localized duplicated genes exhibiting divergent kinetic properties

Cited by 37 publications

References 21 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

Stage and tissue‐specific expression of the alcohol dehydrogenase 1 (Adh‐1) gene during mouse development

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

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