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Oxidative Stress and Inflammation
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Varsha Rana, Dey Parama, Sosmitha Girisa, Choudhary Harsha, Ajaikumar B. Kunnumakkara
Several lifestyle and environmental factors create an imbalance in the oxidant-antioxidant levels, which causes oxidative stress and induces detrimental effect in the cells (Figure 3.1). One of the major lifestyle factors that induce oxidative stress is alcohol consumption. During chronic alcohol consumption, enzymatic system cytochrome P450 2E1 (CYP2E1) generates O2•− and H2O2 efficiently (Albano, 2006). Alcohol also induces CYP2E1 to generate ROS and RNS. The breakdown of alcohol yields acetaldehyde, which is highly toxic and carcinogenic in nature. It also impairs the DNA repair machinery and induces structural as well as functional abnormalities in proteins. It indirectly increases the oxidative stress by interfering with the antioxidant defense system. This system generally neutralizes ROS/RNS; however, antioxidant response is decreased by acetaldehyde formed during alcohol oxidation. As a result, free radicals-induced DNA damage occurs (Seitz and Stickel, 2006). Consistently, another study demonstrated that in an intragastrically fed ethanol-induced alcoholic liver disease model, lipid peroxidation induced the expression of CYP2E1, while the disruption of CYP2E1 expression inhibited oxidative stress and hepatic damage (Gouillon et al., 2000; Albano, 2006).
Garlic
Published in Robert E.C. Wildman, Richard S. Bruno, Handbook of Nutraceuticals and Functional Foods, 2019
Sharon A. Ross, Craig S. Charron
Teyssier et al.35 provided evidence that DADS can be reconverted to diallyl thiosulfinate (allicin) in tissues principally by oxidation arising from cytochrome P450 monooxygenases, and to a limited extent by flavin-containing monooxygenases. Interestingly, their data suggest DADS is preferentially metabolized in human liver to allicin by cytochrome P450 2E1 (CYP2E1). As DADS can also cause autocatalytic CYP2E1 destruction, it is unclear how much allicin might be formed under physiological conditions. Flavin-containing monooxygenases in liver are probably responsible for the oxidization of S-allyl cysteine, among many other sulfur compounds.36 P450 monooxygenases do not appear to be involved in SAC metabolism.
Liver Cancer
Published in Peter G. Shields, Cancer Risk Assessment, 2005
Christopher Loffredo, Christina Frank
Genetic variations among individuals in their capacity to detoxify ethanol may play an additional role in susceptibility to HCC. Ethanol metabolism is mediated by several enzymes, including alcohol dehydrogenase and cytochrome p450 2E1, both of which are encoded by genes known to be polymorphic in populations. Individuals with mutations in one or both of these genes may be at greater or lesser risk from ethanol toxicity depending on the phenotypic consequences of the mutations. A meta-analysis of the RsaI polymorphism in the CYP2E1 gene revealed no association with alcoholic liver disease nor with HCC, while the TaqI allele was significantly less prevalent in persons with alcoholic liver disease compared to healthy subjects (129), suggesting a protective effect. However, there is no direct evidence that the TaqI allele alters the metabolism of ethanol, and the apparent protective effect might be due to linkage disequilibrium with other, unidentified protective genes or factors. More research is clearly needed on this topic.
Inhibitory effect of chlormethiazole on the toxicokinetics of diethylnitrosamine in normal and hepatofibrotic rats
Published in Drug and Chemical Toxicology, 2019
Gaoju Wang, Kang Xiao, Jie Gao, Shan Jiang, Shang Wang, Shijia Weng, Chen Xu, Tong Wang, Hai-Ling Qiao
Cytochrome P450 2E1 (CYP2E1), one of the xenobiotic-metabolizing P450s in the liver, is strongly associated with the metabolism of a wide range of endogenous and exogenous chemicals (Wang et al.2016). It is of interest because of its ability to convert many toxicologically important substrates including ethanol, carbon tetrachloride, acetaminophen, and N-nitrosodimethylamine to reactive intermediates that may elicit organ damage and tumorigenesis (Abdelmegeed et al.2017, Gao et al.2017). Furthermore, it has been shown that CYP2E1 is the most effective catalyst of ethanol oxidation among the human P450 enzymes, and may play an important role in chronic alcohol-induced liver injury (Seitz and Wang 2013). The induction of CYP2E1 expression by chronic alcohol intake enhances its ability to generate reactive oxygen species, enhances the activation of procarcinogens to carcinogens, and increases hepatic necrosis and cellular apoptosis in response to the increased release of the cytokine tumor necrosis factor-alpha (TNF-α), which may contribute to hepatocarcinogenesis (Dinis-Oliveira 2016, Na et al.2017).
Advances in the treatment of severe alcoholic hepatitis
Published in Current Medical Research and Opinion, 2019
Wenjun Wang, Ying Xu, Chang Jiang, Yanhang Gao
There are two major enzyme systems that metabolize EtOH into acetaldehyde (AA) via oxidative degradation. Cytochrome P450 2E1 (CYP2E1) is upregulated by the excessive ingestion of alcohol (10- to 20-fold) and increases the production of reactive oxygen species (ROSs). ROSs cause lipid peroxidation, DNA adduct formation and depletion of glutathione and S-adenosylmethionine, which change the fluidity and permeability of the membrane, produce new antigens to induce antibody formation, and make hepatocytes more susceptible to oxidative stress.
Glabridin attenuates paracetamol-induced liver injury in mice via CYP2E1-mediated inhibition of oxidative stress
Published in Drug and Chemical Toxicology, 2022
Shipra Bhatt, Ankita Sharma, Ashish Dogra, Priyanka Sharma, Amit Kumar, Pankul Kotwal, Swarnendu Bag, Prashant Misra, Gurdarshan Singh, Ajay Kumar, Payare Lal Sangwan, Utpal Nandi
The liver is vulnerable to drug-induced liver injury (DILI) as it is the primary site of drug metabolism. Several drugs are either withdrawn from the market like ibufenac, iproniazid, nimesulide, sulfathiazole, troglitazone, etc. or issued a black box warning by the United States Food and Drug Administration (USFDA) like amiodarone, flutamide, isoniazid, methotrexate, propylthiouracil, etc. due to their potential to cause liver toxicity (DILI rank Dataset, USFDA). However, numerous drugs prone to cause hepatotoxicity are even available in the market because of the non-availability of suitable alternative therapy. DILI is a growing concern worldwide that leads to severe clinical conditions like acute/chronic hepatitis, acute cholestasis, nonalcoholic steatohepatitis, etc. (Kaplowitz 2004). Xenobiotics & chemicals can cause hepatotoxicity and even cause cancer by activating pro-carcinogen by liver enzymes (Hewawasam et al.2004; Jayaweera et al.2017). In this context, cytochrome P450 2E1 (CYP2E1)-mediated oxidation plays a vital role in the direct or indirect elimination of toxic substances from the liver. Despite the beneficial effects of CYP2E1 in the metabolism of alcohol, endogenous fatty acids, etc., diverse nutritional and physiological factors elevate the CYP2E1 enzyme (Wang et al.2003; Khemawoot et al.2007 ). Furthermore, toxic substances are inadvertently bio-activated in the process of CYP2E1-mediated oxidation and lead to oxidative stress (Trafalis et al.2010; Koneru et al.2018). Therefore, CYP2E1 inhibition can be an important target to combat DILI. Research works are ongoing to develop an effective and safe drug, but there is hardly any drug currently available in the market for use. Under these circumstances, plant secondary metabolites, especially flavonoids, have immense potential toward liver protection based on traditional system of medicine (Yang et al.2013; Tsai et al.2018). The present study deals with glabridin, a phytoconstituent from Glycyrrhiza glabra, a widely used medicinal plant. Based on the previous in-vitro studies, glabridin was found to inhibit CYP2E1 in human liver microsomes (Bhatt et al.2021). We aimed here to investigate any protective role of glabridin in DILI through CYP2E1 regulation using paracetamol (PCM)-induced liver injury model. PCM is metabolized by glucuronidation and sulfation (McGill and Jaeschke 2013) and to some extent by CYP2E1 leading to the production of N-acetyl-p-benzoquinone imine (NAPQI). Lower levels of NAPQI are detoxified by reduced glutathione (GSH), but its excessive production at the high dose of PCM exhausts the hepatic GSH level and eventually leads to oxidative stress & liver injury (Dai et al.2006; Bunchorntavakul and Reddy 2013).