Retinoids, omega-hydroxyfatty acids and cytotoxic aldehydes as physiological substrates, and H2-receptor antagonists as pharmacological inhibitors, of human class IV alcohol dehydrogenase.
Kinetic constants of human class IV alcohol dehydrogenase (sigmasigma-ADH) support a role of the enzyme in retinoid metabolism, fatty acid omega-oxidation, and elimination of cytotoxic aldehydes produced by lipid peroxidation. Class IV is the human ADH form most efficient in the reduction of 4-hydroxynonenal (k(cat)/Km: 39,500 mM(-1) min(-1)). Class IV shows high activity with all-trans-retinol and 9-cis-retinol, while 13-cis-retinol is not a substrate but an inhibitor. Both all-trans-retinoic and 13-cis-retinoic acids are potent competitive inhibitors of retinol oxidation (Ki: 3-10 microM) which can be a basis for the regulation of the retinoic acid generation and of the pharmacological actions of the 13-cis-isomer. The inhibition of class IV retinol oxidation by ethanol (Ki: 6-10 mM) may be the origin of toxic and teratogenic effects of ethanol. H2-receptor antagonists are poor inhibitors of human and rat classes I and IV (Ki > 0.3 mM) suggesting a small interference in ethanol metabolism at the pharmacological doses of these common drugs.
Allali-Hassani
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A
Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Peralba
J M
JM
Martras
S
S
Farrés
J
J
Parés
X
X
D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D006801:Humans; D009928:Organ Specificity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012176:Retinoids / Q000378:metabolism*; D013379:Substrate Specificity / Q000187:drug effects
D000447:Aldehydes; D005227:Fatty Acids; D005231:Fatty Acids, Unsaturated; D006635:Histamine H2 Antagonists; D012176:Retinoids; D000426:Alcohol Dehydrogenase; C105552:alcohol dehydrogenase IV