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PubMed1979

Intestinal absorption and metabolism of xenobiotics.

There are five possible processes of intestinal absorption of xenobiotics. These are active transport, passive diffusions, pinocytosis, filtration through "pores," and lymphatic absorption. The passive diffusion is major process for transport of foreign chemicals across the intestine. Though the lymphatic absorption of drugs is not of any major therapeutic significance, the uptake of toxic chemicals such as 3-MC, benzpyrene, and DDT through lymphatics may enhance their toxicity, since they are distributed to other organ systems in the body without being metabolized by liver. A number of factors such as diet, motility of intestine, interference with gastrointestinal flora, changes in the rate of gastric emptying, age of the animal, and dissolution rate of xenobiotic can alter the rate of absorption of chemicals. Liver is the major site of metabolism of xenobiotics, but the contribution of intestinal metabolism of xenobiotic can influence the overall bioavailability of chemicals. The xenobiotic metabolizing enzymes located in endoplasmic reticulum of intestine possess biochemical characteristics similar to that of liver. In general, the rate of metabolism of xenobiotics by intestinal microsomal preparation is lower than that observed with similar hepatic microsomal preparations. The in vitro intestinal metabolism of xenobiotics is affected by several factors including age, sex, diurnal variations, species, and nutritional status of the animal. The intestinal xenobiotic metabolizing enzymes are stimulated by the pretreatment of animals with foreign chemicals, but this depends on the route of administration of chemicals, drug substrate and the animal species used. Rabbit intestinal drug metabolizing enzymes seem to be resistant to induction by foreign chemicals.

Animals↗

PubMed1979

Physiological defence against xenobiotics at their portals of entry to the organism.

The size and relatively high enzyme activity of the liver means that it has the major role in the biotransformation of xenobiotics in mammals. The tissues through which xenobiotics enter the body, lungs, skin, and gastrointestinal tract, have, however, quite a significant capacity for biotransformation, too. Major fractions of small doses of xenobiotics are therefore already metabolized and inactivated before the compounds have penetrated into the body. Most xenobiotics appear in the food and fluid ingested. This emphasises the importance of the gastrointestinal mucous membrane as the first line of defence of body against foreign chemicals. The biotransformation capacity varies with age and environmental chemical exposure, and depends on species and strain.

Age Factors↗

PubMed2025

Human xenobiotic metabolism proteins have full-length and split homologs in the gut microbiome.

Xenobiotics, including pharmaceutical drugs, can be metabolized by both host and microbiota, in some cases by homologous enzymes. We conducted a systematic search for all known human proteins with gut microbial homologs. Because gene fusion and fission can obscure homology detection, we built a pipeline to identify not only full-length homologs, but also cases where microbial homologs were split across multiple adjacent genes in the same neighborhood or operon ("split homologs"). We found that human proteins with full-length gut microbial homologs disproportionately participate in xenobiotic metabolism. While this included many different enzyme classes, short-chain and aldo-keto reductases were the most frequently detected, especially in prevalent gut microbes, while cytochrome P450 homologs were largely restricted to lower-prevalence facultative anaerobes. In contrast, human proteins with split homologs tended to play roles in central metabolism, especially of nucleobase-containing compounds. We identify twelve specific drugs that gut microbial split homologs may metabolize; 2 of these, 6-mercaptopurine by xanthine dehydrogenase and 5-fluorouracil by dihydropyrimidine dehydrogenase, have been recently confirmed in mouse models. This work provides a comprehensive map of homology between the human and gut microbial proteomes, indicates which human xenobiotic enzyme classes are most likely to be shared by gut microorganisms, and finally demonstrates that split homology may be an underappreciated explanation for microbial contributions to drug metabolism.

Humans↗

PubMed1979

Multiplicity of induction patterns of rat liver microsomal mono-oxygenases and other polypeptides produced by administration of various xenobiotics.

Induction of hepatic microsomal mono-oxygenase species after administration of various xenobiotics is a well-documented phenomenon. To examine the number and specific species of rat liver microsomal membrane polypeptides involved in such responses, we have used sodium dodecyl sulphate/polyacrylamide-gel electrophoresis to analyse microsomal fractions from animals treated with a number of important xenobiotics. The following are the principal points to have emerged from this study. 1. A minimum of twelve electrophoretically distinct patterns of induction of haemopolypeptides and other polypeptides could be distinguished after administration, either singly or in certain combinations, of phenobarbital, 3-methylcholanthrene, polychlorinated biphenyls, 2-acetylaminofluorene, safrole (or isosafrole), pregnenolone-16 alpha-carbonitrile and ethanol. The patterns consisted of various permutations of the amounts of eight polypeptides of 47000-56000 mol.wt., of which at least three were haemopolypeptides. The possible identities of these polypeptides, which included species of cytochrome P-450, cytochrome P-448 and epoxide hydratase, are discussed. 2. Agents (3-methylcholanthrene, benzo[a]-pyrene, polychlorinated biphenyls, 2,3,7,8-tetrachlorodibenzo-p-dioxin and beta-naphthoflavone) that result in the induction of cytochrome P-448 caused a marked increase in two polypeptides of 54000 and 56000 mol.wt., whereas safrole and isosafrole induced only the former polypeptide. 3. Administration of 2-acetylaminofluorene resulted in the induction of two polypeptides; evidence is presented that suggests that one of these is a species of epoxide hydratase [cf. Levin, Lu, Thomas, Ryan, Kizer & Griffin (1978) Proc. Natl. Acad. Sci. U.S.A. 75, 3240-3243] ANd that the other may be a novel haemopolypeptide. 4. The overall results emphasize the complexity of the responses exhibited by rat liver microsomal fractions to the administration of xenobiotics.

2-Acetylaminofluorene↗

PubMed1979

The induction of hepatic and extrahepatic xenobiotic metabolism in the rat and ferret by a polychlorinated biphenyl mixture (Aroclor 1254).

1. The effect of a single i.p. dose (500 mg/kg) of a polychlorinated biphenyl mixture (Aroclor 1254) on hepatic and extrahepatic xenobiotic metabolism in male rat, and male and female ferret, was studied. 2. Aroclor 1254 treatment induced hepatic microsomal N-demethylase activities, and cytochrome P-450 and protein content in both rat and ferret. Liver size and aniline 4-hydroxylase were also increased in rat, but not ferret. The polychlorinated biphenyl mixture appeared to be a mixed-type inducer of hepatic xenobiotic metabolism in both species. 3. Aroclor 1254 treatment produced large increases in activities of benzo(a)pyrene hydroxylase and 7-ethoxycoumarin O-deethylase in whole homogenates of the liver, small intestinal mucosa, kidneys and lungs of both species. Maximal stimulation of xenobiotic metabolism occurred in the kidney of both the rat and ferret. In contrast, UDP-glucuronyltransferase activity was only stimulated in liver, intestine and kidney of the rat and in liver and intestine of the ferret. 4. These results suggest a general species similarity in the response to the polychlorinated biphenyl mixture between the rat and ferret.

Animals↗

PubMedDate not supplied

Strain differences in adrenal xenobiotic metabolism in guinea pigs.

Studies were carried out to compare adrenal and hepatic xenobiotic metabolism in various strains of guinea pigs. In all strains studied (Hartley, English Short Hair, NIH, Strain 2, Strain 13), microsomal protein and cytochrome P-450 levels and NADPH-cytochrome c reductase activities were greater in adrenals than livers. Neither adrenal values nor hepatic values for these parameters differed across strains. Ethylmorphine (EM) demethylase and benzo[a]pyrene (BP) hydroxylase activities were also greater in adrenals than livers in all strains. However, the rates of adrenal xenobiotic metabolism were far greater in the highly inbred Strain 2 and Strain 13 guinea pigs than in other strains. In contrast, hepatic metabolism of EM and BP was not strain-dependent. Adrenal steroid 21-hydroxylase activity was also similar in all strains. The results indicate that strain is an important determinant of adrenal but not hepatic xenobiotic metabolism in the guinea pig. In addition, genetic control of adrenal microsomal drug and steroid metabolism appear to be independent of one another.

Adrenal Glands↗

PubMed1978

Biliary excretion of drugs and other xenobiotics.

A vast number and variety of xenobiotics appear in the bile. For some this is a final excretory process, for others it is merely one step in the active enterohepatic circulation. For still others it may be a vital step in a toxicologic or carcinogenic process. During the past ten years there has been a steady accumulation of observations in the literature bearing on biliary excretion mechanisms. Phenomena such as molecular weight thresholds and other aspects of species variation as well as response to inducing agents are described in many papers and much speculation is available as to their meaning. The clinical significance of this work is still somewhat dependent upon results obtained from lower animals, although studies occasionally appear on patients who have temporary bile drainage subsequent to surgery. It is important that efforts persist in obtaining data in humans since extrapolation from lower animals in the area of drug disposition is often precarious. The basic physiological and biochemical mechanism governing the biliary fate of drugs and other xenobiotics have yet to be elucidated fully. Perhaps the use of drugs and other pharmacological tools will hasten progress toward this goal.

Animals↗

PubMedDate not supplied

Maturational changes in adrenal xenobiotic metabolism in male and female guinea pigs.

In young (25-day-old) guinea pigs, adrenal and hepatic benzo[a]pyrene (BP) hydroxylase activities were similar but the rates of ethylmorphine (EM) demethylation were greater in adrenals than liver. Between 25 and 50 days of age no sex differences in adrenal or hepatic enzyme activities were demonstrable. The rates of adrenal BP and EM metabolism increased with age in guinea pigs of both sexes; activities reached significantly higher levels in males than females. In contrast, hepatic metabolism of BP and EM declined with maturation and activities were similar in males and females at all ages. Neither microsomal cytochrome P-450 concentrations no NADPH-cytochrome c reductase activities correlated with the maturational changes or sex differences in xenobiotic metabolism. Adrenal microsomal steroid 21-hydroxylase activity did not change significantly with aging and was not sex-dependent. The results indicate that opposite changes occur in adrenal and hepatic xenobiotic metabolism as a function of aging, resulting in substantially greater adrenal than hepatic activity in sexually mature animals. The data also suggest that adrenal microsomal drug and steroid metabolism are independently regulated.

Adrenal Glands↗

PubMedDate not supplied

Biochemical properties of some microsomal xenobiotic-metabolizing enzymes in rabbit small intestine.

Comparison of xenobiotic-metabolizing enzymes in rabbit small intestinal and hepatic microsomal fractions showed mainly quantitative differences; most of the activities were two to seven times higher in liver than in intestine. However, UDP-glucuronyltransferase activity was higher in intestine than in liver. The apparent absence of benzene hydroxylase in small intestine was the only qualitative difference noticed. Aniline hydroxylase, aminopyrine N-demethylase, and aryl hydrocarbon dydroxylase were characterized in intestinal microsomes and compared to those of liver. Distribution of these enzymes along the entire length of small intestine showed that maximum activities of the enzymes were present in the proximal 60 cm of the intestine. All the enzymes in both tissues required NADPH and O2 for maximum activity and were inhibited by cytochrome c, SKF 525-A, and CO. The in vitro addition of drug substrates to microsomal fractions of both tissues produced typical type I and type II binding spectra. Comparison of the relationships between activities and pH, duration of incubation, and substrate and protein concentration suggested that the rabbit intestinal and hepatic xenobiotic-metabolizing enzymes studied have similar characteristics.

Aminopyrine N-Demethylase↗

PubMed1978

The role of cytochrome P-450 in the toxicity of xenobiotics.

The cytochrome P-450 containing mixed-function oxidase system bound to the ergastoplasmic membrane plays an essential role both in the detoxification as well as in the activation of numerous xenobiotics. In many cases, this enzyme system initiates the formation of reactive electrophilic intermediates (epoxides, free radicals, carbenes) which may induce cytotoxic, mutagenic and carcinogenic effects by reacting with various cell constituents. In most cases, the active metabolites are covalently bound to the proteins and nucleic acids, but the binding to lipids or the initiation of the lipid peroxidation is also important. In the activation of xenobiotics by N-hydroxylation or N-dealkylation an aminoxidase is of special importance which is independent of cytochrome P-450. The intermediates arising from this enzyme reaction frequently become biologically active only after being stabilized by an ester bond.

Aflatoxins↗

PubMed2026

Common xenobiotics modulate gut microbial responses to low‑calorie sweeteners in vitro.

The gut microbiota is implicated in adverse effects associated with low-calorie sweeteners. Yet, the direct impact of sweeteners on gut bacteria remains largely uncharacterized. Here, we report interactions between 25 phylogenetically diverse gut bacterial strains and 39 commercially used sweeteners. We tested these sweeteners individually and in combination with four commonly co-consumed compounds, viz., advantame, caffeine, vanillin, and duloxetine. Three-quarters of the tested sweeteners individually impacted the growth of at least one tested bacterial strain. Further, over 100 interactions were found between sweeteners and the four co-consumed compounds. Isosteviol, a commonly used sweetener-component, and duloxetine, an antidepressant, synergistically inhibited Roseburia intestinalis, a bacterium previously linked to glucose homeostasis, and Parabacteroides merdae, a prevalent commensal linked to healthy microbiota. Proteomic, metabolomic, and genetic analyses indicate altered small molecule transport underpinning this sweetener-drug synergy. The isosteviol-duloxetine combination also modulated metabolism of a synthetic gut bacterial community, leading to increased toxicity to HeLa cells and altered secretion of inflammation-modulatory cytokines IL-6 and IL-8 by Caco-2 cells. Our data warrant further studies on interactions between low-calorie sweeteners and common xenobiotics.

Humans↗

PubMed1977

Dual role of glucuronyl- and sulfotransferases converting xenobiotics into reactive or biologically inactive and easily excretable compounds.

Glucuronyl- and sulfotransferases inactivate a wide variety of hazardous compounds, for example, phenols and dihydrodiols generated during the metabolism of polycyclic hydrocarbons. Our understanding of the firmly membrane-bound glucuronyltransferase is complicated because of their marked activation by membrane perturbants in vitro. Membrane perturbation also occurs in vivo, for example in liver injury caused by CCl4. Moreover, glucuronyltransferases are inducible by xenobiotics. Phenobarbital and 3-methylcholanthrene probably stimulate separate glucuronyltransferases. Sulfotransferases, located in the cytoplasm, often compete with glucuronyltransferases for the same substrates. The generation of 'active sulfate' (PAPS) from cysteine is more likely to be depleted in vivo than the formation of UDP-glucuronic acid generated from carbohydrates. Hence the proportion of sulfate ester/glucuronide may fall with increasing dose of the substrate. Sulfate esters and glucuronides of certain N-hydroxy-arylamines (N-hydroxy-N-acetylaminofluorene, N-hydroxy-phenacetin) are more reactive than the parent compound and bind covalently to cell constituents. Of the two conjugates, sulfate esters are more reactive and thereby more toxic than the corresponding glucuronides. Glucuronides may become toxic in the kidney and bladder where they are highly concentrated.

Animals↗

PubMed1978

Effect of trichlorophenols on xenobiotic metabolism in the rat.

Unlike halogenated benzenes, trichlorophenols did not induce xenobiotic metabolism in the rat. 2,3,5-, 2,3,6-, 2,4,5-, and 2,4,6-Trichlorophenol at doses as high as 400 mg/kg p.o. daily for 14 days did not alter EPN detoxification. Only 2,4,5-trichlorophenol at the highest dose decreased microsomal NADPH-cytochrome c reductase activity and cytochrome P-450 content. In vitro, all 4 isomers inhibited EPN detoxification and the demethylation of p-nitroanisole. UDP-glucuronyltransferase was not altered in vivo and was only slightly inhibited in vitro by 2,3,5- and 2,4,5-trichlorophenol. The compounds were not hepatotoxic as assessed by measurement of hepatic glucose-6-phosphatase and serum sorbitol dehydrogenase.

Animals↗

PubMed1975

Biliary excretion of xenobiotics.

The biliary route is very important for the elimination of some foreign compounds from the body. For many of these compounds, an increase in the rate at which they are excreted into the bile will decrease their toxicity and vice versa. A number of factors which are known to alter the biliary excretion of xenobiotics, as well as the current concepts of the physiological mechanisms responsible for the excretion of foreign compounds, have been enumerated. However, much remains still to be understood; essentially nothing is known at the subcellular level about the biliary excretion of foreign compounds. It has recently been concluded that our knowledge of the biliary excretion of compounds is about 40 years behind that of the renal excretion mechanism.

Aging↗

PubMed1979

Studies on the incubation mixtures for the in vitro mutagenesis test with metabolic activation (microsomal assay). Behaviour of mixed function oxidase and lipid peroxidation in the presence of some xenobiotics.

The effect of some xenobiotics on microsomal mixed function oxidase and lipid peroxidation, in mice, in incubation mixtures for the in vitro mutagenesis test with metabolic activation was studied. Aniline 1 or 2 mM and aminopyrine 0.38 or 8.33 mM completely inhibited the lipid peroxidation with small protection of the monooxygenase. Styrene 50 or 100 mM inhibited to a lesser extent the lipid peroxidation with marked increase in the inactivation of the monooxygenase. By a technique based on successive additions of fresh microsomes it was possible to evaluate the part of the inactivation due to enzyme denaturation and that due to inhibition. EDTA 40 mM was not able to protect from inactivation in the presence of aniline 1mM. Data of this type could be utilized to obtain more reliable results of in vitro mutagenesis tests with metabolic activation by suitably managing the enzyme activity in the incubation mixtures in order to keep it as constant as possible.

Aminopyrine↗

PubMed1979

[Comparative study of effects of the tyrosine-copper(II) complex on xenobiotic hydroxylation and lipid peroxidation].

It has been found that NADPH-dependent hydroxylation of dimethylaniline, aniline, p- and o-nitroanisol and lipid peroxidation is inhibited by the tyrosine-copper (II) complex (low molecular weight analog of superoxide dismutase), which is indicative of a possibility of superoxide radicals formation in these reactions. The inhibition of the above-mentioned reactions with Tyr2-Cu2+ is less pronounced or absent, if cumole hydroperoxide is used as cosubstrate instead of NADPH. Differences in the Tyr2-Cu2+ complex effects on the cumule hydroperoxide-dependent xenobiotics hydroxylation and lipid peroxidation catalyzed by various forms of cytochrome P-450, e. g. microsomal, soluble and incorporated into liposomes, have been found. The data obtained suggest that the efficiency of the inhibitory effect of the Tyr2-Cu2+ complex depends on the type of cosubstrates (NADPH, cumole hydroperoxide) and substrates used as well as on the form of cytochrome P-450.

Animals↗

PubMed1979

[Accelerated microsomal DNA synthesis under the influence of xenobiotics and chemical carcinogens].

Injection of 3,4-benz(a)pyrene, methyl nitrosourea and phenobarbital into healthy mice of the C3HA line results in a rapid, sharp increase of [14C]-thymidine incorporated into liver microsomal DNA, accompanied by a suppression of nuclear DNA synthesis. In the liver of neoplastic mice and in the ascite cells of hepatoma 22A the system of microsomal DNA synthesis was insensitive to the injection of methyl nitrosourea. Cycloheximide and puromycin, which strongly inhibited nuclear DNA synthesis, had no effect on the synthesis of microsomal DNA. Stimulation of [14C]-thymidine incorporation into microsomal DNA after injection of methyl nitrosourea and 3,4-benz(a)pyrene may be accounted for not only by an increase of the DNA reparation processes, since caffeine, the inhibitor of post-replicatory reparation of DNA, did not eliminate the induction of microsomal DNA synthesis in the liver. Hydroxyurea in combination with methyl nitrosourea and phenobarbital significantly suppressed the synthesis of nuclear DNA in the liver and did not affect the synthesis of mtDNA; the stimulating effects of these inducers on the synthesis of microsomal DNA was thereby removed. This is indicative of independence of synthesis of microsomal DNA on that of nuclear DNA and mtDNA. Different specific radioactivities of microsomal, nuclear and mtDNAs in the regenerating mouse liver on the 5th, 10th and 15th post-hepatectomy days may be due to different metabolic stability of these DNAs. A possible role of microsomal DNA as a xenobiotic system component is discussed.

Animals↗

PubMedDate not supplied

[Effect of x-ray contrast substances on the metabolism of xenobiotics and steroid hormones by rat liver microsomes].

Uro- and cholecystographic contrast media are shown to be capable of changing the rate of oxidative hydroxylation of amidopyrine and steroid hormones. The degree and duration of the diminishing rate of the xenobiotics and steroids metabolism are determined by concentrations of the X-ray contrast media in hepatic cells and the rate of their clearance.

Aminopyrine↗