Excessive vitamin A toxicity in mice genetically deficient in either alcohol dehydrogenase Adh1 or Adh3.
Alcohol dehydrogenase (ADH) deficiency results in decreased retinol utilization, but it is unclear what physiological roles the several known ADHs play in retinoid signaling. Here, Adh1, Adh3, and Adh4 null mutant mice have been examined following acute and chronic vitamin A excess. 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. 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. When mice were propagated for one generation on a retinol-supplemented diet containing 10-fold higher vitamin A than normal, Adh3 and Adh4 mutants had essentially the same postnatal survival to adulthood as wild-type (92-95%), but only 36% of Adh1 mutants survived to adulthood with the remainder dying by postnatal day 3. Adh1 mutants surviving to adulthood on the retinol- supplemented diet had elevated serum retinol signifying a clearance defect and elevated aspartate aminotransferase indicative of increased liver damage. These findings indicate that ADH1 functions as the primary enzyme responsible for efficient oxidative clearance of excess retinol, thus providing protection and increased survival during vitamin A toxicity. ADH3 plays a secondary role. Our results also show that retinoic acid is not the toxic moiety during vitamin A excess, as Adh1 mutants have less retinoic acid production while experiencing increased toxicity.
Molotkov
Andrei
A
Gene Regulation Program, Burnham Institute, La Jolla, CA 92037, USA.
Fan
Xiaohong
X
Duester
Gregg
G
D000426:Alcohol Dehydrogenase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000445:Aldehyde Oxidoreductases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D005260:Female; D006128:Growth / Q000187:drug effects; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018811:Maternal Exposure; D051379:Mice; D014801:Vitamin A / Q000378:metabolism / Q000633:toxicity*
D014801:Vitamin A; D000426:Alcohol Dehydrogenase; C105552:alcohol dehydrogenase IV; C020145:formaldehyde dehydrogenase (glutathione); D000445:Aldehyde Oxidoreductases