The mammalian gut microbiota interact extensively with the host through metabolic exchange and co-metabolism of substrates. Such metabolome-metabolome interactions are poorly understood, but might be implicated in the aetiology of many human diseases. In this paper, we assess the importance of the gut microbiota in influencing the disposition, fate and toxicity of drugs in the host, and conclude that appropriate consideration of individual human gut microbial activities will be a necessary part of future personalized health-care paradigms.

Gut microorganisms, mammalian metabolism and personalized health care

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.1840060330

Genetic polymorphism of human liver alcohol and aldehyde dehydrogenases, and their relationship to alcohol metabolism and alcoholism.

After ingestion, disulfiram (DSF) is rapidly converted, probably in the stomach, to its bis (diethyldithiocarbamato) copper complex. Consequently, absorption and distribution via the gastrointestinal mucosa into the blood might involve both the parent drug and its copper complex. In the blood, both compounds are rapidly degraded to form diethyldithiocarbamic acid (DDC), which is unstable and is further degraded to form diethylamine and carbon disulphide. DDC is also a substrate of phase II metabolism, which involves formation of diethyldithiomethylcarbamate (Me-DDC) and the glucuronic acid of DDC. Me-DDC also undergoes oxidative biotransformation to diethylthiomethylcarbamate (Me-DTC), which is further oxidized to its corresponding sulphoxide and sulphone metabolites. Me-DTC may to act as a suicide inhibitor with a preference for the mitochondrial low Km isozyme of aldehyde dehydrogenases (ALDH 1), whereas the two S-oxidized metabolites, especially the sulfone metabolite, are more potent inhibitors not only of ALDH 1, but also of the cytosolic high Km isozyme of ALDH (ALDH 2). The inhibitory reaction between the enzyme and each of the three metabolites is characterized by a covalent adduct formation, probably with the cysteine residue at the active site of the enzymes. The adduct formed is nonreducible at a physiological concentration of glutathione, and inactivation in the presence of this endogenous tripeptide was increased by action in vitro of the sulphoxide and sulphone metabolites. Those findings are all in concordance with the in vivo observations made on DSF. In human volunteers treated with increasing doses of DSF and challenged with ethanol between each of the dosage periods, the mean plasma concentrations of Me-DTC at steady state were proportional to the DSF doses given. There was also a close relationship between increased oxidative metabolic formation of Me-DTC, high oxidative formation of acetaldehyde, and the full complements of a valid disulfiram ethanol reaction (DER). Consequently, Me-DTC in plasma may not only serve as a marker of the oxidative metabolic function of the liver, but also of the therapeutic effectiveness of the treatment in subjects at steady state. Obviously, there is a need for individual dose-titration regimens. In patients with alcohol-related severe hepatocellular damage, the oxidative P 450 catalyzed formation of the Me-DTC and probably also of its sulfoxide and sulphone metabolites is impaired, and thus inactivation of ALDH activity in the liver appears to be delayed or even completely absent. The consequence for the patient may be an insufficient DER.(ABSTRACT TRUNCATED AT 400 WORDS)

A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites.

Consumption of large quantities of alcoholic beverages leads to disturbances in the intestinal absorption of nutrients including several vitamins. The inhibition of the absorption of sodium and water caused by alcohol contributes to the tendency in alcoholics to develop diarrhoea. Excessive alcohol consumption (even a single episode) can result in duodenal erosions and bleeding and mucosal injury in the upper jejunum. An increased prevalence for bacterial overgrowth in the small intestine may contribute to functional and/or morphological abnormalities of this part of the gut and also to non-specific abdominal complaints in alcoholics. The mucosal damage caused by alcohol increases the permeability of the gut to macromolecules. This facilitates the translocation of endotoxin and other bacterial toxins from the gut lumen to the portal blood, thereby increasing the liver's exposure to these toxins and, consequently, the risk of liver injury. The results of recent experimental studies support the assumption that alcohol significantly modulates the mucosal immune system of the gut.

Effect of alcohol consumption on the gut.

International Encyclopedia of Pharmacology and Therapeutics

https://www.gastrojournal.org/article/S0016-5085(83)80065-1/pdf

Immunohistochemical Localization of Alcohol Dehydrogenase in the Human Gastrointestinal Tract

Biology of disease. Alcoholism and aldehydism: new biomedical concepts.

Antibodies against human liver alcohol dehydrogenase (ADH) were produced in rabbits. Peroxidase-labeled protein-A with diaminobenzidine as substrate was used to detect anti-ADH binding in human tissue thin sections. In the kidney, ADH was localized in the epithelia of the tubuli; glomeruli and collecting tubules appeared negative. In prostata and epididymis, the epithelia stained strongly. In the testes, the seminiferous epithelium and the Leydig cells stained strongly. In the ovary and uterus only faint staining was observed. The ADH-content of the adrenal gland was low, but was higher in the cortex than in the medulla. In the pancreas, the Langerhans islets exhibited particularly high ADH concentrations. In the brain, ADH was localized in neurons of the cerebral cortex, hypothalamus, infundibular stalk of the pituitary, and Purkinje cells of the cerebellum. In summary, ADH could be localized primarily in cells known as targets of ethanol toxicity.

http://www.whilesciencesleeps.com/pdf/637.pdf

Immunohistochemical localization of alcohol dehydrogenase in human kidney, endocrine organs and brain

Human alcohol dehydrogenase (ADH; alcohol:NAD+ oxidoreductase, EC 1.1.1.1) occurs in multiple forms, which exhibit distinct electrophoretic mobilities and enzymatic properties. The homogeneous isoenzymes beta 1 beta 1 and gamma 1 gamma 1 were isolated from livers of Caucasians with "typical" ADH phenotype by double ternary complex affinity chromatography and ion exchange chromatography. The differences between the beta 1 and gamma 1 subunits were determined by structural analysis of all tryptic peptides from the carboxymethylated proteins. The human beta 1 and gamma 1 chains differ at 21 of the 373 positions (5.6%). Ten tryptic peptides account for the differences. All residue substitutions are compatible with one-base mutations and result in largely unaltered properties, but five lead to charge differences. Sixteen substitutions are at positions corresponding to the catalytic domain of the well-known horse enzyme; five correspond to the coenzyme-binding domain. Substitutions adjacent to important regions may correlate with differences in coenzyme binding, substrate specificities, and active-site relationships. The residue replacements between the beta 1 and gamma 1 subunits of human ADH are not identical to the known substitutions between ethanol-active (E) and steroid-active (S) subunits of horse ADH. Thus, the duplication leading to human beta 1 and gamma 1 subunits is separate and different from that leading to equine E and S subunits. Both duplications are likely to have occurred after the ancestral separation of human and equine ADH. Of the 21 residues that are different between beta 1/gamma 1, 13 in gamma 1 but only 6 in beta 1 are identical to those of the horse E chain. This suggests a closer relationship between gamma 1 and E, although beta 1 in man and E in the horse are the subunits recovered in highest yield from liver ADH preparations. Consequently, in these two mammalian species, relative activities of genes for an isoenzyme family appear to be different.

Human alcohol dehydrogenase: structural differences between the beta and gamma subunits suggest parallel duplications in isoenzyme evolution and predominant expression of separate gene descendants in livers of different mammals

The alpha subunit of human liver alcohol dehydrogenase has been submitted to structural analysis. Together with earlier work on the beta and gamma subunits, the results allow conclusions on the relationship of all known forms of the class I type of the enzyme. Two segments of the alpha subunit were determined; one was also reinvestigated in the beta and gamma subunits. The results establish 11 residue replacements among class I subunits in the segments analyzed and show that the alpha, beta, and gamma protein chains each are structurally distinct in the active site regions, where replacements affect positions influencing coenzyme binding (position 47; Gly in alpha, Arg in beta and gamma) and substrate specificity (position 48; Thr in alpha and beta, Ser in gamma). Residue 128, previously not detected in beta and gamma subunits, corresponds to a position of another isozyme difference (Arg in beta and gamma, Ser in alpha). The many amino acid replacements in alcohol dehydrogenases even at their active sites illustrate that in judgements of enzyme functions absolute importance of single residues should not be overemphasized. Available data suggest that alpha and gamma are the more dissimilar forms within the family of the three class I subunits that have resulted from two gene duplications. The class distinction of alcohol dehydrogenases previously suggested from enzymatic, electrophoretic, and immunological properties therefore also holds true in relation to their structures.

R. Bühler

Papers

Immunohistochemical Localization of Alcohol Dehydrogenase in the Human Gastrointestinal Tract

Biology of disease. Alcoholism and aldehydism: new biomedical concepts.

Immunohistochemical localization of alcohol dehydrogenase in human kidney, endocrine organs and brain

Human alcohol dehydrogenase: structural differences between the beta and gamma subunits suggest parallel duplications in isoenzyme evolution and predominant expression of separate gene descendants in livers of different mammals

Structural relationships among class I isozymes of human liver alcohol dehydrogenase