Modulation of alcohol dehydrogenase and ethanol metabolism by sex hormones in the spontaneously hypertensive rat. Effect of chronic ethanol administration

Rachamin, Gloria; Macdonald, J. A.; Wahid, S F Abdul; Clapp, J J; Khanna, J. M.; Israel, Yedy

doi:10.1042/bj1860483

Cited by 129 publications

(43 citation statements)

References 24 publications

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“…The emergence of gender differences in ADH activity coincides with sexual development: a relative increase in ADH activity in females is not detected until the sixth week of age, the age at which rodents reach sexual maturity, and remains elevated thereafter (Rao et al, 1997). Second, estrogen increases hepatic ADH activity, whereas testosterone decreases it (Rachamin et al, 1980;Harada et al, 1998). Similar to ADH, estrogen also Fig.…”

Section: Discussionmentioning

confidence: 89%

Pregnane X Receptor–Humanized Mice Recapitulate Gender Differences in Ethanol Metabolism but Not Hepatotoxicity

Spruiell

Gyamfi

Yeyeodu

et al. 2015

J Pharmacol Exp Ther

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Both human and rodent females are more susceptible to developing alcoholic liver disease following chronic ethanol (EtOH) ingestion. However, little is known about the relative effects of acute EtOH exposure on hepatotoxicity in female versus male mice. The nuclear receptor pregnane X receptor (PXR; NR1I2) is a broad-specificity sensor with species-specific responses to toxic agents. To examine the effects of the human PXR on acute EtOH toxicity, the responses of male and female PXRhumanized (hPXR) transgenic mice administered oral binge EtOH (4.5 g/kg) were analyzed. Basal differences were observed between hPXR males and females in which females expressed higher levels of two principal enzymes responsible for EtOH metabolism, alcohol dehydrogenase 1 and aldehyde dehydrogenase 2, and two key mediators of hepatocyte replication and repair, cyclin D1 and proliferating cell nuclear antigen. EtOH ingestion upregulated hepatic estrogen receptor a, cyclin D1, and CYP2E1 in both genders, but differentially altered lipid and EtOH metabolism. Consistent with higher basal levels of EtOH-metabolizing enzymes, blood EtOH was more rapidly cleared in hPXR females. These factors combined to provide greater protection against EtOH-induced liver injury in female hPXR mice, as revealed by markers for liver damage, lipid peroxidation, and endoplasmic reticulum stress. These results indicate that female hPXR mice are less susceptible to acute binge EtOH-induced hepatotoxicity than their male counterparts, due at least in part to the relative suppression of cellular stress and enhanced expression of enzymes involved in both EtOH metabolism and hepatocyte proliferation and repair in hPXR females.

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Section: Discussionmentioning

confidence: 89%

Pregnane X Receptor–Humanized Mice Recapitulate Gender Differences in Ethanol Metabolism but Not Hepatotoxicity

Spruiell

Gyamfi

Yeyeodu

et al. 2015

J Pharmacol Exp Ther

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“…Studies in rodents have shown that ethanol can increase ADH activity in male rats by reducing testosterone levels (Rachamin et al 1980). The doses of ethanol delivered to rats or mice via the use of liquid diets does not have significant effects on liver ADH.…”

Section: Alcohol Dehydrogenasesmentioning

confidence: 99%

Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology

et al. 2004

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Alcohol dehydrogenase (ADH) and mitochondrial aldehyde dehydrogenase (ALDH2) are responsible for metabolizing the bulk of ethanol consumed as part of the diet and their activities contribute to the rate of ethanol elimination from the blood. They are expressed at highest levels in liver, but at lower levels in many tissues. This pathway probably evolved as a detoxification mechanism for environmental alcohols. However, with the consumption of large amounts of ethanol, the oxidation of ethanol can become a major energy source and, particularly in the liver, interferes with the metabolism of other nutrients. Polymorphic variants of the genes for these enzymes encode enzymes with altered kinetic properties. The pathophysiological effects of these variants may be mediated by accumulation of acetaldehyde; high-activity ADH variants are predicted to increase the rate of acetaldehyde generation, while the low-activity ALDH2 variant is associated with an inability to metabolize this compound. The effects of acetaldehyde may be expressed either in the cells generating it, or by delivery of acetaldehyde to various tissues by the bloodstream or even saliva. Inheritance of the high-activity ADH β2, encoded by the ADH2*2 gene, and the inactive ALDH2*2 gene product have been conclusively associated with reduced risk of alcoholism. This association is influenced by gene–environment interactions, such as religion and national origin. The variants have also been studied for association with alcoholic liver disease, cancer, fetal alcohol syndrome, CVD, gout, asthma and clearance of xenobiotics. The strongest correlations found to date have been those between the ALDH2*2 allele and cancers of the oro-pharynx and oesophagus. It will be important to replicate other interesting associations between these variants and other cancers and heart disease, and to determine the biochemical mechanisms underlying the associations.

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“…Many previous studies (8,12,13,16,(20)(21)(22) showed increases in liver ADH activity during uremia produced by partial nephrectomy after stress induced by immobilization and after hypophysectomy. Further, uremia and various forms of stress in man all result in a fall in plasma testosterone levels.…”

Section: Effect Of Testosterone On Liver Adh Activities In Orchiectommentioning

confidence: 99%

Effect of Sex Hormones on Rat Liver Cytosolic Alcohol Dehydrogenase Activity.

Harada

Tachiyashiki

Imaizumi

1998

Journal of Nutritional Science and Vitaminology, J Nutr Sci Vit

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Modulation of alcohol dehydrogenase and ethanol metabolism by sex hormones in the spontaneously hypertensive rat. Effect of chronic ethanol administration

Cited by 129 publications

References 24 publications

Pregnane X Receptor–Humanized Mice Recapitulate Gender Differences in Ethanol Metabolism but Not Hepatotoxicity

Pregnane X Receptor–Humanized Mice Recapitulate Gender Differences in Ethanol Metabolism but Not Hepatotoxicity

Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology

Effect of Sex Hormones on Rat Liver Cytosolic Alcohol Dehydrogenase Activity.

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