Disease relevance of Adh7

• Formaldehyde toxicity studies revealed that only Adh3 -/- mice had a significantly reduced LD50 value [1].
• In addition, the finding of endogenous RA and class IV ADH mRNA in the craniofacial region has implications for the mechanism of fetal alcohol syndrome [2].

High impact information on Adh7

• Thus, the observed ethanol-induced reduction in RA may be caused by ethanol inhibition of retinol oxidation catalyzed by class IV ADH [3].
• Redundant roles for Adh1 and Adh4 in retinoic acid production may explain the apparent normal development of mutant mice [1].
• 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 [1].
• During neurulation, RA and class IV ADH mRNA were colocalized in the craniofacial region, trunk, and forelimb bud [2].
• Class IV ADH mRNA was detected in cranial neural crest cells and craniofacial mesenchyme as well as trunk and forelimb bud mesenchyme [2].

Chemical compound and disease context of Adh7

• Acute retinol toxicity, assessed by determination of the LD(50) value, was greatly increased in Adh1 mutants and moderately increased in Adh3 mutants, but only a minor effect was observed in Adh4 mutants [4].
• Excessive vitamin A toxicity in mice genetically deficient in either alcohol dehydrogenase Adh1 or Adh3 [4].

Biological context of Adh7

• Genetics and ontogeny of alcohol dehydrogenase isozymes in the mouse: evidence for a cis-acting regulator gene (Adt-i) controlling C2 isozyme expression in reproductive tissues and close linkage of Adh-3 and Adt-i on chromosome 3 [5].
• Reproductive tissue ADH-C2 phenotypes were inherited in a normal Mendelian fashion among F2 progeny of an F1 (LII x C57BL/Go) x C57BL/Go backcross as though controlled by a single cis-acting regulator locus (designated Adt-1) with two alleles: Adt-1a (presence of ADH-C2) and Adt-1b (absence or low activity of ADH-C2) [5].
• The complete mouse class IV ADH coding region was found in nine exons spanning a 14-kb region [6].
• To enable genetic studies on the function of this enzyme and regulation of its gene, we have screened a genomic library and isolated the mouse class IV ADH gene (Adh3) [6].
• Genetic analysis also confirmed the close linkage of Adh-1 (encoding liver and kidney ADH-A2) and Adh-3 (encoding stomach ADH-C2) to within 0.3 centimorgans on the mouse genome [7].

Anatomical context of Adh7

• In situ hybridization studies on mouse stomach indicated that class IV ADH transcripts were abundant in the mucosal epithelium but absent from the muscular layer [8].
• Genetic analysis of a proposed cis-acting temporal locus (Adh-3t), which regulates alcohol dehydrogenase C2 (ADH-C2) activity in mouse epididymis extracts, among F1 (ddN X BALB/c) X ddN male backcross progeny provided evidence for genetic distinctness between the structural (Adh-3) and temporal (Adh-3t) loci on chromosome 3 [7].
• Detection of class IV ADH mRNA, but not class I or class III, coincided with the onset of RA synthesis, being absent in egg cylinder embryos but present in the posterior mesoderm of late primitive streak embryos [2].
• In situ hybridization revealed high levels of both class I and class IV ADH messenger RNAs in adrenal glands of 16.5-day mouse embryos and adults [9].
• Abundant class IV ADH protein was detected in the embryonic adrenal as well as in the zona glomerulosa and zona fasiculata of the adult adrenal cortex [9].

Associations of Adh7 with chemical compounds

• 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 [1].
• Following an acute dose of retinol (50 mg.kg(-1)), metabolism of retinol to retinoic acid in liver was reduced 10-fold in Adh1 mutants and 3.8-fold in Adh3 mutants, but was not significantly reduced in Adh4 mutants [4].
• Here, Adh1, Adh3, and Adh4 null mutant mice have been examined following acute and chronic vitamin A excess [4].
• This apparent down-regulation of class IV ADH expression during keratinocyte terminal differentiation provides evidence that the basal layer of the epidermis may be the primary site of local retinoic acid synthesis needed for retinoid signaling in the skin [10].

Other interactions of Adh7

• By the use of the BXD series of recombinant inbred strains and by crosses between C57BL and CSB, it was possible to map the gene to the distal part of chromosome 3 by demonstration of linkage to a gene for cadmium resistance, cdm, as well as to the Adh-3 locus [11].
• The mutation, called rostral cerebellar malformation, rcm, has been located on chromosome (Chr) 3 between the alcohol dehydrogenase-3 (Adh-3) complex and varitint waddler-J (VaJ) [12].
• Electrophoretic and activity variants of ADH-C2 among inbred strains of mice have been used to localise the gene encoding this enzyme (Adh-3) and a closely linked temporal locus (Adh-3-t) on chromosome 3 of this organism [13].
• Evidence is presented for a fourth allele of Aox-2 and a third allele of Adh-3 [14].

Analytical, diagnostic and therapeutic context of Adh7

• In Northern blot analyses, mouse class IV ADH mRNA was abundant in the stomach, eye, skin, and ovary, thus correlating with the expression pattern for the mouse Adh-3 gene previously determined by enzyme analysis [8].
• Gene targeting was used to create knockout mice for either Adh1 or Adh4 [15].

References