Ethanol Oxidation by Hepatic Microsomes: Adaptive Increase after Ethanol Feeding

Lieber, Charles S.; DeCarli, Leonore M.

doi:10.1126/science.162.3856.917

Cited by 538 publications

(175 citation statements)

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“…Oxidation of ethanol via ADH explains various metabolic effects of ethanol but does not account for the tolerance. Until late 1960s, Lieber and DeCarli suggested that the microsomal ethanol oxidizing system, mainly involving cytochrome P4502E1 (CYP2E1), is responsible for alcohol oxidation [67][68][69]. This suggestion was then followed by extensive experimental studies of ethanol oxidation by P450 [70][71][72][73] due to its key role in toxicology, such as acidosis and fatty liver disease.…”

Section: Ethanol Oxidationmentioning

confidence: 99%

Recent density functional theory model calculations of drug metabolism by cytochrome P450

Wang

Han

2012

Coordination Chemistry Reviews

132

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Section: Ethanol Oxidationmentioning

confidence: 99%

Recent density functional theory model calculations of drug metabolism by cytochrome P450

Wang

Han

2012

Coordination Chemistry Reviews

132

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“…On the other hand, if individuals with the abnormality persist in drinking alcohol for psychological and/or environmental reasons, prolonged elevation of acetaldehyde could lead to a formation of toxic materials related to alcohol addiction (Davis and Walsh, 1970). Several investigators have suggested that a hepatic ethanol-inducible microsomal alcohol dehydrogenase and ADH-z play a substantial role in the handling of a high level of alcohol over a long period of time (Orme-Johnson and Ziegler, 1965;Lieber and DeCarli, 1968;Li et al, 1977). Whether or not genetic differences of microsomal and ADH-Tr exist between Orientals and American Indians, remains unanswered.…”

Section: Resultsmentioning

confidence: 99%

Molecular basis of difference in alcohol metabolism between Orientals and Caucasians

Yoshida

1982

Jap J Human Genet

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SummaryThe human cytosol alcohol dehydrogenase(ADH) controlled by ADH2 locus is known to be polymorphic. Most Caucasians have the usual enzyme consisting of the usual ~1 subunit, while nearly 90~ of Orientals have the atypical /~2 subunit. At the physiological pH, the cytosol enzyme activity of the atypical liver is much higher than that of the typical liver. It has been suggested that a high frequency of acute alcohol intoxication among Orientals could be related to the rapid accumulation of acetaldehyde due to the atypical ADH. Human liver aldehyde dehydrogenase (ALDH) is also polymorphic. Virtually all Caucasians have two major isozymes, i.e., ALDH-1 and ALDH-2, while about 50~ of Orientals have only ALDH-1, missing ALDH-2 component. Since ALDH-2 has high affinity to acetaldehyde, the high incidence of alcohol sensitivity in Orientals could be related to the accumulation of acetaldehyde due to the lack of ALDH-2 component. The usual ADH homodimer ~1/71 and the atypical homodimer ~2/~2 were purified to homogeneity. The specific activity of the atypical enzyme was nearly three orders of magnitude higher than the usual enzyme at the physiological pH. The usual enzyme was rapidly inactivated by iodoacetate, indicating an existence of the "active site cysteine'" in the molecule. In contrast, the atypical enzyme was resistant against the iodoacetate inactivation. Peptide mapping analysis revealed that the active site cysteine in the usual ~1 subunit is replaced by histidine in the atypical 82 subunit. In the usual ~1~1 enzyme, like horse enzyme, the catalytic Zn is expected to link to the sensitive cysteine at position 47, histidine at position 67, and cysteine at presumably position 174, thus making up the active site. In contrast, the active site of the atypical ~2~2 enzyme is expected to consist of the catalytic Zn linked to histidine at position 47, histidine at position 67, and cysteine at position around 174. The functional abnormalities of the atypical enzyme can be correlated to its molecular abnormality. 55

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“…En los seres humanos, se han aislado 12 genes que codifican distintos tipos de ALDH (ALDH1-ALDH12) con secuencias de aminoá-cidos bien diferenciadas. Los loci para algunos de esos genes están en diferentes cromosomas (9,11,12,17) (Kitson y Weiner, 1996). Sin embargo, las isoenzimas hepáticas son solamente dos, la ALDH1 citosólica y la ALDH2 mitocondrial; el resto se encuentra distribuido en otros tejidos (Kitson y Weiner, 1996).…”

Section: Metabolismo Hepático Del Acetaldehído: La Aldehido Deshidrogunclassified

Alcohol y metabolismo humano

et al. 2002

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Ethanol Oxidation by Hepatic Microsomes: Adaptive Increase after Ethanol Feeding

Cited by 538 publications

References 15 publications

Recent density functional theory model calculations of drug metabolism by cytochrome P450

Recent density functional theory model calculations of drug metabolism by cytochrome P450

Molecular basis of difference in alcohol metabolism between Orientals and Caucasians

Alcohol y metabolismo humano

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