Contribution to first-pass metabolism of ethanol and inhibition by ethanol for retinol oxidation in human alcohol dehydrogenase family--implications for etiology of fetal alcohol syndrome and alcohol-related diseases.
The alcohol dehydrogenase (ADH) family is involved in the metabolism of both ethanol and retinoids. To quantitatively assess the potential contributions to first-pass metabolism of ethanol and the ethanol interference with retinoid homeostasis, saturation kinetics for ethanol oxidation as well as inhibition kinetics by ethanol for all-trans-retinol oxidation of human class I alpha alpha, beta1beta1, beta2beta2, gamma1gamma1, class II pi pi, class III chi chi, and class IV mu mu were evaluated and compared. Class I and class II ADHs exhibited substrate inhibition with inhibition constants ranging over 250-720 mM (except gamma1gamma1) ethanol. Class IV ADH displayed no appreciable inhibition up to 1 M ethanol. Activity of the class III enzyme (190 nM subunit) was undetectable at 250 mM ethanol. The kinetic simulations indicate that the hepatic pi pi and the gastric mu mu can most effectively contribute to first-pass metabolism of alcohol. The Michaelis constant (Km), turnover number (k(cat)), and catalytic efficiency (k(cat)/Km) for retinol oxidation relative to that for ethanol oxidation in class I, class II, and class IV ADHs ranged over 0.00022-1.3, 0.071-0.48, and 0.24-650, respectively. Ethanol was a competitive inhibitor against retinol for class I, II, and IV ADHs with apparent inhibition constants ranging over 0.037-11 mM, indicating that retinoic acid synthesis through the ADH pathways can be tremendously blocked during social/heavy drinking. These findings support the notion that first-pass metabolism of alcohol may occur mainly in the liver through class II pi pi and that cellular retinoid signaling may be perturbed by ethanol via ADH pathways.
Han
C L
CL
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.
Liao
C S
CS
Wu
C W
CW
Hwong
C L
CL
Lee
A R
AR
Yin
S J
SJ
D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors* / Q000145:classification; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000378:metabolism* / Q000494:pharmacology; D063647:Fetal Alcohol Spectrum Disorders / Q000503:physiopathology*; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D010084:Oxidation-Reduction; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000378:metabolism; D014801:Vitamin A / Q000378:metabolism*
D004791:Enzyme Inhibitors; D014801:Vitamin A; D000431:Ethanol; D014212:Tretinoin; D000426:Alcohol Dehydrogenase