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Metabolism of Terpenoids in Animal Models and Humans
Published in K. Hüsnü Can Başer, Gerhard Buchbauer, Handbook of Essential Oils, 2020
(R)-(+)-Pulegone is present in essential oils of Lamiaceae. Hedeoma pulegioides and Mentha pulegium, both commonly called pennyroyal, contain essential oils that are chiefly pulegone (O'Neil, 2006; Bornscheuer et al., 2014). Pennyroyal herb had been used for inducing menstruation and abortion. In higher doses, however, it may result in central nervous system toxicity, gastritis, hepatic and renal failure, pulmonary toxicity, and death. Commercially available, pennyroyal oils have a pulegone content >80% and are both hepatotoxic and pneumotoxic in mice (Engel, 2003). Though pulegone has been used for flavoring food and oral hygiene products, the pulegone content in foods and beverages is restricted by EU law. At nontoxic concentrations, pulegone is oxidized selectively at the 10-position and further metabolized into menthofuran. In vitro data show that this metabolic pathway is mainly catalyzed by human CYP2E1, and to a lesser extent by CYP1A2 and CYP 2C19 (Khojasteh-Bakht et al., 1999). Alternatively, it may be reduced to menthone, which has been detected in trace levels in urine samples. It might be possible that pulegone is also reduced at the carbonyl group first. Consequently, pulegol is either reduced very efficiently to menthol or rearranged to 3-p-menthen-8-ol (Engel, 2003) (Figure 10.23). In rats, three major pathways have been identified: (a) hydroxylation followed by glucuronidation, (b) reduction to menthone and hydroxylation, and (c) conjugation with glutathione and further metabolism (Chen et al., 2001; Ferguson et al., 2007).
Garlic
Published in Robert E.C. Wildman, Richard S. Bruno, Handbook of Nutraceuticals and Functional Foods, 2019
Sharon A. Ross, Craig S. Charron
A block in nitrosamine bioactivation may reflect changes in several enzymes. However, substantial evidence points to the involvement of CYP2E1.108,109 An autocatalytic destruction of CYP2E1 may account for some of the chemoprotective effects of DAS, and possibly other allyl sulfur compounds.110 Variation in the concentration and overall activity of CYP2E1 may be an important variable in the degree of protection provided by garlic and associated allyl sulfur components.
Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
The CYP2E1 gene maps to chromosome 10q26.3 and contains nine exons. The CYP2E1 gene is conserved in chimpanzee, rhesus monkey, dog, cow, mouse, and rat. The predominant expression site of CYP2E1 is in the liver with a moderate abundance. Other expression sites include lung (Hukkanen et al. 2002), esophagus, small intestine (Warner and Gustafsson 1994), brain (Upadhya et al. 2000), nasal mucosa (Kazakoff et al. 1994), and pancreas (Norton et al. 1998). There is an interindividual variation of an order of magnitude as well as a racial difference.
The nuclear receptor REV-ERBα regulates CYP2E1 expression and acetaminophen hepatotoxicity
Published in Xenobiotica, 2022
Li Zhang, Fugui Zhang, Yifei Xiao, Jianhao Du, Xingwang Zhang, Min Chen, Baojian Wu
Due to a critical role of CYP2E1 in xenobiotic metabolism and bioactivation, the regulatory mechanisms for its expression and activity are of great interest. Recently, several clock genes and nuclear receptors have been demonstrated to regulate CYP2E1 expression. For instance, cryptochrome 1 (CRY1) regulates rhythmic expression of CYP2E1 through repression of the transcriptional activity of hepatocyte nuclear factor 1 α (HNF1α) in humans and mice (Matsunaga et al. 2008). Circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like protein-1 (BMAL1) can induce Cyp2e1 transcription (Matsunaga et al. 2008). Period 1 (PER1) interacts with the complex of HNF1α/CREB and increases the binding activity of HNF1α to the Cyp2e1 promoter, thereby enhancing the transcription of Cyp2e1 in mouse liver (Ge et al. 2021). Small heterodimer partner (SHP) up-regulates Cyp2e1 expression via repressing DEC2 (differentiated embryonic chondrocyte gene 2)-HNF1α axis (Zhang et al. 2018). Identification of the regulators for CYP2E1 would facilitate new strategies for improving efficacy and reducing toxicities of its substrate drugs.
The development and hepatotoxicity of acetaminophen: reviewing over a century of progress
Published in Drug Metabolism Reviews, 2020
Mitchell R. McGill, Jack A. Hinson
CYP2E1 is of major interest in human toxicity because of the consumption of alcoholic beverages. In 1986, Seeff et al. (1986) reported on six alcoholics who developed toxicity after taking APAP and reviewed 19 similar case reports. In 1995, Zimmerman and Maddrey (1995) reported on an additional 67 alcoholic patients who developed liver toxicity after taking moderate doses of APAP. The increased toxicity of APAP was attributed to induction of CYP2E1 in alcoholics and increased production of the toxic metabolite as a result (Zimmerman and Maddrey 1995). However, the possibility that APAP may be toxic in alcoholics at moderate doses has been disputed by Prescott (2000) and by Rumack (2002, 2004). The problems in obtaining proper controls make it difficult to know if alcoholics are more susceptible to APAP hepatotoxicity. Nevertheless, it is considered a risk factor when decisions are made whether to treat with NAC (Schmidt et al. 2002).
Evaluation of oxidative stress via protein expression of glutathione S-transferase and cytochrome p450 (CYP450) ısoenzymes in psoriasis vulgaris patients treated with methotrexate
Published in Cutaneous and Ocular Toxicology, 2018
Ozge Akbulak, Ayse Serap Karadag, Necmettin Akdeniz, Seyma Ozkanli, Emin Ozlu, Ebru Zemheri, Serpil Oguztuzun
CYP2E1 is one of the key enzymes in drug metabolism, and it is particularly responsible for liver toxicity related to ethanol and acetaminophen26. Cederbaum A26,27 showed that the hepatotoxic effects of ethanol and acetaminophen were related to ROS/RNS produced upon their metabolization by CYP2E1. Similarly, it was found to be responsible for the hepatotoxic effects of MTX metabolized in the liver28. A relationship was found between CYP450 enzymes in drug metabolism and carcinogenesis due to drug resistance or UV sensitivity8. Phillips et al.29 have reported that MTX increases CYP-related peroxidase production in the T cells, thereby directing them to apoptosis, and they suggested that due to the fact that monocytes had a threefold higher GSH antoxidant system, they were less affected. In another study, Smith et al.20 showed that CYP1A1, CYP1A2, CYP1B1, CYP2C18, NQO-1, GSTP1, gamma-glutamyl cysteine synthetase, GPx-1, cyclooxygenase-2 and haemooxygenase-1 expressions were induced by topical coal tar; CYP26, NADPH P450 reductase and GSTP1 HO-1 expressions were induced by all-trans retinoic acid; and CYP3A5 expression was induced by clobetasol 17-propionate. The authors concluded that CYP1A1 and CYP1A2 expressions were inhibited by all-trans retinoic acid, while gamma-glutamyl cysteine synthetase and MRP1 expressions were inhibited by clobetasol 17-propionate.