Effect of l-carnitine supplementation on xenobiotic-metabolizing hepatic enzymes exposed to methanol
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Liver enzyme
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In addition to its role in digestion of food in the gastrointestinal tract, the intestinal microflora is also capable of biotransforming numerous drugs. Likewise, the intestinal microflora may significantly modulate xenobiotic‐induced toxicity by either activating or inactivating xenobiotics via metabolism. To date, most investigations of xenobiotic metabolism have focused not only on metabolism in host tissues, but the modulation of the pharmacological activity of drugs by the intestinal microflora. Despite its importance, the presumed role of intestinal microflora metabolism in xenobiotic‐induced toxicity has been understudied. Therefore, it is appropriate to briefly review our current situation, and state which research in xenobiotic metabolism by intestinal microflora, particularly in the field of toxicology, is needed.
Xenobiotic
Microbial Metabolism
Gut microflora
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The liver is the central organ for xenobiotic metabolism (XM) and is regulated by nuclear receptors such as CAR and PXR, which control the metabolism of drugs. Here we report that gut microbiota influences liver gene expression and alters xenobiotic metabolism in animals exposed to barbiturates.By comparing hepatic gene expression on microarrays from germfree (GF) and conventionally-raised mice (SPF), we identified a cluster of 112 differentially expressed target genes predominantly connected to xenobiotic metabolism and pathways inhibiting RXR function. These findings were functionally validated by exposing GF and SPF mice to pentobarbital which confirmed that xenobiotic metabolism in GF mice is significantly more efficient (shorter time of anesthesia) when compared to the SPF group.Our data demonstrate that gut microbiota modulates hepatic gene expression and function by altering its xenobiotic response to drugs without direct contact with the liver.
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Pregnane X receptor
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(1995). Xenobiotic Metabolism in Brain. Drug Metabolism Reviews: Vol. 27, No. 3, pp. 419-448.
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This chapter identified the fundamental principles of foreign compound (xenobiotic) modification by the body and discusses: how xenobiotics enter, circulate, and leave the body; the sites of metabolism of the xenobiotic within the body; the chemistry and enzymology of xenobiotic metabolism; the bioactivation as well as inactivation of xenobiotics during metabolism; and the variations in xenobiotic metabolism resulting from prior or concomitant exposure to xenobiotics and from physiological factors.
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1. Precision-cut liver slices are a valuable in vitro model system to study the metabolism and toxicity of xenobiotics. Liver slices retain tissue architecture so that all cell types are present and intercellular communication between the various cell types is retained.2. Precision-cut liver slices from humans and other species have been used to study pathways of phase I (e.g. cytochrome P450-dependent biotransformations) and II (e.g. conjugation with D-glucuronic acid, sulphate and glutathione) metabolism of a wide range of xenobiotics.3. Liver slices can also be employed to investigate the induction and inhibition of xenobiotic metabolizing enzymes and to obtain kinetic data on the rates of metabolism of xenobiotics.4. Precision-cut liver slices from humans and other species have been used to study the toxicity of a wide variety of xenobiotics. Toxicity can be assessed by various techniques including gene expression, morphological examination and a wide range of biochemical endpoints.5. Precision-cut liver slices can be utilized to examine species differences in hepatic xenobiotic metabolism and xenobiotic-induced toxicity, thus permitting comparisons between animal species and humans.
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