The etiology of alcoholism in women is no longer a question of nature or nurture. Most observers would agree that alcoholism, both male and female, is mediated by genetic factors. The question is how much of the variance is explained by genetic factors and to what degree is this genetically mediated disorder moderated by personal characteristics of the woman. Among the most salient personal characteristics moderating the genetic vulnerability may be factors such as age, ethnicity, and presence of psychiatric comorbidity. Cultural factors and familial environmental factors are most likely predictors as well. Therefore, the chapter will discuss the genetic epidemiology of alcoholism in women. Genetic heterogeneity will be discussed and evidence presented that suggests the existence of two forms of alcoholism in women: one more environmentally determined and one more influenced by genetic mediation. Evidence for the existence of a genetic diathesis in women will be presented, noting extant literature involving twin and adoption designs. Suggestions for what might be transmitted from generation to generation (e.g., neurobiological factors, temperament) with special reference to preadolescent and adolescent girls will also be discussed.

Recent Developments in Alcoholism

Significant differences that exist between the sexes affect the prevalence, incidence and severity of a broad range of diseases and conditions. Men and women also differ in their response to drug treatment. It is therefore essential to understand these reactions in order to appropriately conduct risk assessment and to design safe and effective treatments. Even from that modest perspective, how and when we use drugs can result in unwanted and unexpected outcomes. This review summarizes the sex-based differences that impact on pharmacokinetics, and includes a general comparison of clinical pharmacology as it applies to men, women and pregnant women. Sex-related or pregnancy-induced changes in drug absorption, distribution, metabolism and elimination, when significant, may guide changes in dosage regimen or therapeutic monitoring to increase its effectiveness or reduce potential toxicity. Given those parameters, and our knowledge of sex differences, we can derive essentially all factors necessary for therapeutic optimization. Since this is a rapidly evolving area, it is essential for the practitioner to review drug prescribing information and recent literature in order to fully understand the impact of these differences on clinical therapeutics.

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Sex Differences in Pharmacokinetics and Pharmacodynamics

The distribution of the human liver alcohol dehydrogenase, ADH2, and aldehyde dehydrogenase, ALDH2, genotypes in 21 different populations comprising Mongoloids, Caucasoids, and Negroids was determined by hybridization of the amplified genomic DNA with allele-specific oligonucleotide probes. Whereas the frequency of the ADH1(2) allele was found to be relatively high in the Caucasoids, Mexican Mestizos, Brazilian Indios, Swedish Lapps, Papua New Guineans and Negroids, the frequency of the ADH2(2) gene was considerably higher in the Mongoloids and Australian Aborigines. The atypical ALDH2 gene (ALDH2(2)) was found to be extremely rare in Caucasoids, Negroids, Papua New Guineans, Australian Aborigines and Aurocanians (South Chile). In contrast, this mutant gene was found to be widely prevalent among the Mongoloids. Individuals possessing the abnormal ALDH2 gene show alcohol-related sensitivity responses (e.g. facial flushing), have the tendency not to be habitual drinkers, and apparently suffer less from alcoholism and alcohol-related liver disease.

Distribution of ADH2 and ALDH2 genotypes in different populations

https://www.gastrojournal.org/article/0016-5085(94)90772-2/pdf

Alcohol and the liver: 1994 update.

Background: The enhanced vulnerability of women to develop alcohol-related diseases may be due to their higher blood alcohol levels after drinking, but the mechanism for this effect is debated.

Methods: Sixty-five healthy volunteers of both genders drank 0.3 g of ethanol/kg of body weight (as 5%, 10%, or 40% solutions) postprandially. Blood alcohol concentrations were monitored by breath analysis and compared with those after intravenous infusion of the same dose. First-pass metabolism was quantified (using Michaelis-Menten kinetics) as the route-dependent difference in the amount of ethanol reaching the systemic blood. Gastric emptying was assessed by nuclear scanning after intake of 300 μCurie of technetium-labeled diethylene triamine pentacetic acid in 10% ethanol. The activities of alcohol dehydrogenase isozymes were assessed in 58 gastric biopsies, using preferred substrates for γ-ADH (acetaldehyde) and for ς-ADH (m-nitrobenzaldehyde) and a specific reaction of χ-ADH (glutathione-dependent formaldehyde dehydrogenase).

Results: Women had less first-pass metabolism than men when given 10% or 40%, but not 5%, alcohol. This was associated with lower gastric χ-ADH activity; its low affinity for ethanol could explain the greater gender difference in first-pass metabolism with high rather than with low concentrations of imbibed alcohol. Alcohol gastric emptying was 42% slower and hepatic oxidation was 10% higher in women. A 7.3% smaller volume of alcohol distribution contributed to the higher ethanol levels in women, but it did not account for the route-dependent effects.

Conclusions: The gender difference in alcohol levels is due mainly to a smaller gastric metabolism in females (because of a significantly lesser activity of χ-ADH), rather than to differences in gastric emptying or in hepatic oxidation of ethanol. The concentration-dependency of these effects may explain earlier discrepancies. The combined pharmacokinetic differences may increase the vulnerability of women to the effects of ethanol.

Gender differences in pharmacokinetics of alcohol.

As various isoenzymes of gastric alcohol dehydrogenase exist and as the effect of sex and age on these enzymes is unknown, this study measured the activity of gastric alcohol dehydrogenase at high and low ethanol concentrations in endoscopic biopsy specimens from a total of 290 patients of various ages and from 10 patients with chronic alcoholism. Gastric alcohol dehydrogenase was also detected by immunohistological tests in biopsy specimens from 40 patients by the use of a polyclonal rabbit antibody against class I alcohol dehydrogenase. A significant correlation was found between the immunohistological reaction assessed by the intensity of the colour reaction in the biopsy specimen and the activity of alcohol dehydrogenase measured at 580 mM ethanol. While alcohol dehydrogenase activity measured at 16 mM ethanol was not significantly affected by age and sex, both factors influenced alcohol dehydrogenase activity measured at 580 mM ethanol. Young women below 50 years of age had significantly lower alcohol dehydrogenase activities in the gastric corpus and antrum when compared with age matched controls (SEM) (6.4 (0.7) v 8.8 (0.6) nmol/min/mg protein; p < 0.001 and 6.0 (1.3) v 9.5 (1.3) nmol/min/mg protein; p < 0.001). Over 50 years of age this sex difference was no longer detectable, as high Km gastric alcohol dehydrogenase activity decreases with age only in men and not in women. In addition, extremely low alcohol dehydrogenase activities have been found in gastric biopsy specimens from young male alcoholics (2.2 (0.5) nmol/min/mg protein), which returned to normal after two to three weeks of abstinence. The activity of alcohol dehydrogenase in the human stomach measured at 580 mM ethanol is decreased in young women, in elderly men, and in the subject with alcoholism. This decrease in alcohol dehydrogenase activity may contribute to the reduced first pass metabolism of ethanol associated with raised ethanol blood concentrations seen in these people.

https://gut.bmj.com/content/gutjnl/34/10/1433.full.pdf

Human gastric alcohol dehydrogenase activity: effect of age, sex, and alcoholism.

Genotyping of mitochondrial aldehyde dehydrogenase (ALDH I) was performed in enzymatically amplified DNA of 20 Chinese, Japanese and South Korean families (85 individuals) and in 113 unrelated persons by employing allele-specific oligonucleotide probes and dot blot hybridization. Genotyping individuals with phenotypic deficiency of ALDH I activity always showed the presence of at least one mutant allele. The data are compatible with a model assuming dominant inheritance of the mutant allele, which we have previously suggested on the basis of a population study.

Inheritance of mitochondrial aldehyde dehydrogenase: genotyping in Chinese, Japanese and South Korean families reveals dominance of the mutant allele.

Population genetic and family studies on aldehyde dehydrogenase deficiency and alcohol sensitivity.

A rare case of human liver cytosolic aldehyde dehydrogenase (isozyme II) variation discovered in a Chinese autopsy liver specimen is reported. While the major isozyme band was nearly absent, several additional minor bands were observed on isoelectric focusing gel. Rabbit antibodies to purified human liver ALDH II showed immunological cross-reactivity for the variant enzyme bands. The existence of additional minor bands indicates the presence of tetramer hybrid forms made up of normal and variant monomers. The observed abnormality may represent the heterozygous form of ALDH II variation. A similar variant was also detected in erythrocytes of a male Thai student.

R. Eckey

Papers

Human gastric alcohol dehydrogenase activity: effect of age, sex, and alcoholism.

Inheritance of mitochondrial aldehyde dehydrogenase: genotyping in Chinese, Japanese and South Korean families reveals dominance of the mutant allele.

Population genetic and family studies on aldehyde dehydrogenase deficiency and alcohol sensitivity.

Detection and partial characterization of a variant form of cytosolic aldehyde dehydrogenase isozyme.

Basis of aldehyde dehydrogenase deficiency in Orientals: immunochemical studies.