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Biotransformation of Xenobiotics in Living Systems—Metabolism of Drugs: Partnership of Liver and Gut Microflora
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
The primary site of alcohol metabolism is the liver. The main pathway of ethanol metabolism involves its conversion to acetaldehyde, an oxidative reaction that is catalyzed by enzymes known as alcohol dehydrogenases. In a second reaction mediated by aldehyde dehydrogenase, acetaldehyde is oxidized to acetate (Fig. 6.7). Other enzymes, such as cytochrome P450 (e.g., CYP2E1), metabolize a small fraction of the ingested ethanol (Edenberg, 2007). Some drugs may inhibit the activity of aldehyde dehydrogenase leading to the accumulation of acetaldehyde during ethanol ingestion, which is associated with flushing, nausea and vomiting, palpitations and dyspnea. The well-known interaction is between disulfiram and ethanol. Because of its ability to cause these extremely unpleasant symptoms, disulfiram may be used to effectively treat alcohol dependence (Kitson, 1977). Other drugs that can cause disulfiram-like effects when administered concurrently with ethanol include chloramphenicol, furazolidone (Karamanakos et al., 2007) and some of cephalosporin antibiotics (Ren et al., 2014).
Metabolism and Toxicity of Occupational Neurotoxicants: Genetic, Physiological, and Environmental Determinants
Published in Lucio G. Costa, Luigi Manzo, Occupatinal Neurotoxicology, 2020
Stefano M. Candura, Luigi Manzo, Anna F. Castoldi, Lucio G. Costa
Chronic ethanol intake stimulates hepatic oxidative metabolism, due to induction of CYP2E1 and other microsomal enzymes, but may inhibit certain Phase II reactions such as glucuronidation, methylation and GSH conjugation. Additionally, in chronic alcoholics ethanol causes liver damage, which leads to lowered levels of xenobiotic-metabolizing enzymes.81,84 Extrahepatic enzymes and cofactors can also be affected. In the rat, under subchronic exposure conditions that mimicked combined exposure of workers consuming moderate amounts of alcoholic beverages, ethanol and styrene induced 23 and 30% depletion of brain GSH, respectively. Concomitant administration of the toxicants caused a cerebral GSH depletion in the order of 60%.34
Carbon Monoxide Formation Due To Metabolism of Xenobiotics
Published in David G. Penney, Carbon Monoxide, 2019
Kubic et al. (1974) showed that pretreatment of rats with phenobarbital or 3-methylcholanthrene failed to alter COHb levels after a single i.p. administration of DCM, 3 mmol/kg. This indicated that neither cytochrome P-450s 2B and 2C nor cytochrome P-450s 1A1 and 1A2 plays an essential role as catalyst of the DCM oxidation. In studies on the oxidation of DCM to CO, Guengerich et al. (1991) observed variation in Vmax among four human liver microsomal preparations, but when these data were compared to rates of chlorzoxazone 6-hydroxylation, a correlation coefficient of 0.94 was found. Cytochrome P-450 2E1 (CYP2E1) is the primary catalyst of chlorzoxazone 6-hydroxylation in human liver (Peter et al., 1990). CYP2E1 is induced by a variety of agents including isoniazid, ethanol, acetone, pyrazole, imidazole, benzene, xylenes, and trichloroethylene (Ingelman-Sundberg and Jörnvall, 1984; Koop and Coon, 1986; Ryan et al., 1985, 1986). Increased rates of the oxidation of DCM to CO as measured by COHb formation was observed by pretreatment with these and other inducers provided they are no longer present to compete with the DCM for oxidative metabolism (Table 1). After simultaneous uptake of DCM and a substrate of CYP2E1 such as ethanol, methanol, butanol, acetone, chloroform, tetrachloromethane, benzene, m-, p- or o-xylene, styrene, ethylben-zene, tetrahydrofuran, aniline, pyrazole, trichloroethylene, isoniazid, or acetaminophen, the DCM-derived COHb formation is decreased or completely blocked. Some examples are given in Figure 1. This inhibition is well known after simultaneous exposure to DCM and ethanol (Balmer et al., 1976; Ciuchta et al., 1979; Glatzel et al., 1987). An inhibition was also demonstrated in rats pretreated with toluene, 5 mmol/kg i.p., 30 min prior to an exposure to 5000 ppm DCM (Ciuchta et al., 1979) and in rats after simultaneous oral administration of both toluene and DCM, and if DCM was administered 12 h after toluene uptake, but the mean COHb formation in blood was significantly enhanced by prior administration of toluene at 20 to 28 h (Figure 2). Similar biphasic effects in dependence of the time interval between the uptake of CYP2E1 inducer and DCM were observed in rats following the combined exposure to ethanol or other aromatic compounds with DCM (Pankow et al., 1990, 1991b).
Characterization of cytochrome P450s (CYP)-overexpressing HepG2 cells for assessing drug and chemical-induced liver toxicity
Published in Journal of Environmental Science and Health, Part C, 2021
Si Chen, Qiangen Wu, Xilin Li, Dongying Li, Nan Mei, Baitang Ning, Montserrat Puig, Zhen Ren, William H. Tolleson, Lei Guo
The gene expression of CYP2E1 in primary human hepatocytes was higher than in HepaRG and CYP2E1-overexpressing HepG2 cells (Tables 1 and 2). CYP2E1 enzyme expression is inducible by many of its substrates (e.g. alcohol) with complex mechanisms including transcriptional regulation.63 In addition, CYP2E1 is inducible under diverse pathophysiological conditions, including diabetes, obesity, fasting, and alcoholic liver disease.64 The high expression level of CYP2E1 observed in the primary hepatocytes could be explained by the lifestyle and disease conditions of the donors (Supplemental Table 2). For example, half of the donors were obese (BMI ≥ 30) and 4 out of the 10 donors consumed alcohol frequently.
Construction of polysaccharide scaffold-based perfusion bioreactor supporting liver cell aggregates for drug screening
Published in Journal of Biomaterials Science, Polymer Edition, 2022
Lei Cao, Huicun Zhao, Mengyuan Qian, Chuxiao Shao, Yan Zhang, Jun Yang
Acetaminophen and isoniazid were employed to assess the sensitivity to hepatotoxic drugs of hepatocytes cultured in the bioreactor. The classical drug toxicity evaluation model (collagen-sandwich) and pectin/alginate blend scaffold (3 D static) were used as control groups. The results of the CCK-8 assay showed that when the concentrations of acetaminophen are 5 μM and 10 μM, the cell viability in the 3 D dynamic group was reduced by 38% and 54%, respectively. While the cell activity was decreased by 21% and 36% in the 3 D static group, and the cell activity reduction ratio of the collagen-sandwich group was 13% and 21%. Similar results were obtained when hepatocytes were cultured in WE containing isoniazid. Compared to the collagen-sandwich group (cell survival rate decreased by 10% and 20%) and the 3 D static group (cell survival rate decreased by 18% and 26%), the hepatocyte viability in the 3 D dynamic group was reduced by 28% and 42%, respectively (Figure 5B). These results indicated that the 3 D dynamic culture significantly improved the metabolic ability of hepatocytes to acetaminophen and isoniazid compared with those in collagen-sandwich and 3 D static groups. In the liver, the metabolism of acetaminophen and isoniazid is mediated almost exclusively by CYP450 2E1 (CYP2E1) [66, 67]. As shown in Figure S3, the mRNA expression of CYP2E1 of hepatocytes in the 3 D dynamic group was significantly up-regulated after being treated with APAP, while that was slightly decreased after being treated with isoniazid. It has been revealed that APAP hepatotoxicity was associated with the up-regulated expression of CYP2E1 [68], and the expression and activity of CYP2E1 are inhibited upon or after isoniazid metabolism [69, 70]. Therefore, these results indicated a responsive increase in the expression of drug-metabolizing enzymes. Furthermore, only the hepatocytes cultured in a bioreactor exhibited a significant concentration-dependent sensitivity to hepatotoxicity drugs.
Regulation of cytochrome P450 expression by microRNAs and long noncoding RNAs: Epigenetic mechanisms in environmental toxicology and carcinogenesis
Published in Journal of Environmental Science and Health, Part C, 2019
Dongying Li, William H. Tolleson, Dianke Yu, Si Chen, Lei Guo, Wenming Xiao, Weida Tong, Baitang Ning
In ways that are analogous to the examples presented above, miRNAs can inhibit CYP2E1 gene expression by targeting its mRNA transcript or by targeting transactivators that regulate its transcription. miR-378a-5p (previously identified as miR-378) binds to the CYP2E1 3′-UTR and decreases the levels of CYP2E1 protein and enzymatic activity via translational repression.103 Interestingly, miR-378-5p downregulates CYP2E1 at the mRNA level without affecting the rate of CYP2E1 mRNA degradation, suggesting the possibility of pre- or co-transcriptional regulation of CYP2E1. The underlying mechanism for this observation is still unclear. Cytoplasmic miR-552 inhibits CYP2E1 translation via binding to its MRE in the 3′-UTR of the CYP2E1 mRNA transcript.104 Meanwhile, miR-552 present in the nucleus hybridizes with the cruciform structure of the CYP2E1 promoter via its nonseed region and prohibits RNA Pol II-dependent CYP2E1 transcription. Thus, the novel dual negative regulatory mechanisms exploited by miR-552 provide evidence of both transcriptional and translational control of CYP2E1 expression. Moreover, miRNAs can reduce CYP2E1 expression indirectly by silencing transactivators of CYP2E1. Utilizing next-generation sequencing (NGS) data from acetaminophen-treated HepaRG cells, Yu et al.110 conducted a thorough search of differentially expressed miRNAs and mRNAs of genes involved in acetaminophen hepatoxicity, including drug metabolizing enzymes and NRs. The expression of HNF1A and NR1I2, well-known transcription factors that stimulate CYP gene expression, was suppressed by acetaminophen in HepaRG cells. These investigators then showed that hsa-miR-320a and hsa-miR-877-5p bind to MREs present in the 3′-UTRs of HNF1A and NR1I2 mRNA transcripts and decrease the mRNA and protein levels of both. The suppressing effects of hsa-miR-320a and hsa-miR-877-5p on CYP2E1 were comparable to those of siRNAs specific for HNF1A and NR1I2. miRNA-dependent mechanisms influence both the constitutive and induced expression of CYP2E1. Hsa-miR-214-3p targets the coding region of CYP2E1 mRNA and suppresses constitutive CYP2E1 expression in HepaRG cells.102 Although ethanol treatment at 200 mM for 24 h had little impact on expression of miR-214-3p in HepG2 cells, overexpression of miR-214-3p upon ethanol induction increased CYP2E1 mRNA and protein levels by 85% and 37% respectively, compared to negative control. This effect is particularly critical as CYP2E1 induction by alcohol enhances the toxicity of acetaminophen overdose and activation of pro-carcinogens to carcinogens in both initiation and promotion stages of alcohol-related liver cancer.140,141 Inter-personal differences in miR-214-3p expression due to genetic variation or drug and environmental exposure may result in differential susceptibility in xenobiotic-induced, CYP2E1-mediated liver toxicity and carcinogenesis; thus, miR-214-3p might serve as a biomarker or as a therapeutic target for such adverse effects.