Metabolism of Terpenoids in Animal Models and Humans
K. Hüsnü Can Başer, Gerhard Buchbauer in Handbook of Essential Oils, 2020
3-Carene is found in various Pinaceae essential oils: (+)-3-Carene is a major compound of Pinus palustris essential, and (−)-3-carene of Pinus sylvestris. It is used as raw material in perfumery (Bornscheuer et al., 2014). In rabbits, 3-carene is metabolized into 3-caren-9-ol and presumably via 3-caren-10-ol, and further oxidized into carboxylic and dicarboxylic acid products (Ishida et al., 1981, 2005). Another metabolic pathway takes place via opening of the methylene bridge to m-mentha-4,6-dien-8-ol with subsequent dehydrogenation of the cyclohexene ring to m-cymen-8-ol (Ishida, 2005). In vitro experiments with human liver microsomes revealed 3-caren-10-ol and 3-carene epoxide as metabolites (Figure 10.4). Hydroxylation was catalyzed by CYP2B6, CYP2C19, and CYP2D6, whereas epoxidation could be attributed to CYP1A2 (Duisken et al., 2005). Interestingly, neither of these two metabolites, nor the supposed hydrolysis product of the epoxide, 3-carene-3,4-diol, could be detected in rabbit or human urine, yet (Ishida, 2005; Schmidt et al., 2013, 2015). A recent study (Schmidt et al., 2015) identified chaminic acid as a new metabolite in human urine after oral intake of 3-carene (Figure 10.4). Moreover, Schmidt et al. suggested that dihydrochaminic acid and carene-3,4,9-triol are additional metabolites of 3-carene in humans (Schmidt et al., 2015).
Overview of the Biotransformation of Antiepileptic Drugs
Carl L. Faingold, Gerhard H. Fromm in Drugs for Control of Epilepsy:, 2019
Once epoxides are formed by mixed-function oxidases, several things can happen to them. One, they can be hydrolyzed enzymatically to dihydrodiols. The enzyme responsible for the hydration is epoxide hydrolase. This enzyme is located predominantly in liver microsomes, but it is also found in hepatic cell cytosol.11 The microsomal hydrolase is inducible by many xenobiotics, and it possibly exists in multiple forms. Second, the epoxide can rearrange nonenzymatically to form phenols or dihydrodiols. Third, the epoxide can interact with glutathione (see below). Fourth, the epoxide may ultimately react with tissues. The tissue-epoxide interaction can be the source of important drug toxicity, e.g., tissue necrosis or carcinogenesis. Just which route of biotransformation a given drug takes depends on many factors, not the least of which is its chemical structure.
Perspectives on Assessment of Risks from Dermal Exposure to Polycyclic Aromatic Hydrocarbons
Rhoda G. M. Wang, James B. Knaak, Howard I. Maibach in Health Risk Assessment, 2017
Epoxidation is the first activating oxidation reaction. Arene-epoxides are electrophilic and can spontaneously form covalent bonds with nucleophilic centers in biological macromolecules such as DNA, RNA, and protein. The position and stereochemistry of the epoxidation varies among PAHs. For BaP, the intermediate formed is a 7,8-epoxide. This reaction is catalyzed by P-450 IA1 isoform. Following hydrolysis by epoxide hydrolase, a second oxidation results in the 7, 8-diol 9,10 epoxide, often termed a “bay-region” dihydrodiol epoxide due to the physical positions of carbons 9 and 10. This second oxidation is catalyzed by a different microsomal enzyme, epoxide hydrolase. For most PAHs characterized, formation of specific enantiomers of diol epoxides, principally the (S,R,R,S) form, produces the ultimate carcinogenic metabolite (Platt et al., 1990). For a number of PAHs, the bay region diol epoxide is presumably the molecular species that forms mutagenic adducts with cellular DNA (Slaga et al., 1981). Although not all polycyclic aromatic structures contain a bay region, epoxidation by cytochrome P-450 I can nonetheless produce reactive molecular species. For example, metabolites of indeno[1,2,3-cd]pyrene from rat liver microsomes are mutagenic in S. typhimurium assays. In PAHs that lack a bay region, such as indeno[1,2,3 cd]pyrene, formation of K-region epoxides appear to be responsible for adduct formation and mutagenicity (Bucker et al., 1979; Rice et al., 1985).
Susceptibility to the acute toxicity of acrylonitrile in streptozotocin-induced diabetic rats: protective effect of phenethyl isothiocyanate, a phytochemical CYP2E1 inhibitor
Published in Drug and Chemical Toxicology, 2021
Fang Li, Ying Dong, Rongzhu Lu, Bobo Yang, Suhua Wang, Guangwei Xing, Yuanyue Jiang
This study demonstrates that STZ-induced diabetic rats were susceptible to AN-induced acute toxicity, and this sensitivity was due to enhanced CYP2E1 activity. Additionally, the lower rates of survival in acetone (CYP2E1 inducer)-pretreated rats also helped investigate the underlying mechanisms of the susceptibility to AN in diabetic rats. Two chemical moieties or potentially their combination mediate the acute toxic effects of AN, namely, the parent AN molecule and the metabolically released cyanide. CYP2E1 is the main enzyme responsible for AN epoxidation, contributing to cyanide formation (Wang et al. 2010). Therefore, genetic variability in CYP2E1 expression and the ensuing variation in CYP2E1 activity unsurprisingly play a critical role in human susceptibility to AN (Bolt et al. 2003). Notably, CYP2E1 activity is modified by diabetes, fasting, prolonged starvation, obesity, and a high-fat diet, as well as in alcoholic and non-alcoholic diseases (Miller and Yang 1984, Khemawoot et al. 2007, Leon-Buitimea et al. 2012). Thus, these conditions may heighten the risk of AN-induced toxicity (Bolt et al. 2003). By utilizing an STZ-induced diabetic rat model, we provide novel insight into the heightened sensitivity to AN in a diabetic state. The present findings further corroborate earlier observations on enhanced benzene and thioacetamide hepatotoxicity in diabetic rats (Costa et al. 1999, Wang et al. 2000).
Lung macrophages: current understanding of their roles in Ozone-induced lung diseases
Published in Critical Reviews in Toxicology, 2020
O3 has also been implicated in the production of unique ozonation products including 1-palmitoyl-2-(9′-oxo-nonanoyl)-glycerophosphocholine (PON-GPC) as well as nonspecific auto-oxidation products such as 5β, 6β-epoxy-cholesterol (β-epoxide) and secosterols (Seco A and B) (Almstrand et al. 2015). PON-GPC is known to compromise macrophage viability (Uhlson et al. 2002) and induce release of proinflammatory mediators via activation of the 5-lipoxygenase pathway (Zemski Berry and Murphy 2016). Macrophage receptors of the SRA family (scavenger receptor A-I/II (SRA-I/II) and MARCO) have been implicated in the scavenging of oxidized lipids. Dahl and colleagues mechanistically established that β-epoxide and PON-GPC fail to induce neutrophil recruitment in MARCO-deficient mice implicating MARCO as a likely receptor for β-epoxide and PON-GPC. They further reported that mice deficient in MARCO as well as SRA-I/II had more robust O3-induced lung injury suggesting a protective role for MARCO and SRA-I/II in O3-induced lung injury (Dahl et al. 2007). CD36, a class B macrophage scavenger receptor, is known to bind to a number of oxidized lipoproteins and phospholipids, and CD36 expression is elevated in mice upon O3 exposure (Valacchi et al. 2007). Moreover, genetic deletion of CD36 protects against lung inflammation (Robertson et al. 2013; Mumaw et al. 2016).
LC-MS/MS based detection and characterization of covalent glutathione modifications formed by reactive drug of abuse metabolites
Published in Xenobiotica, 2019
R. Allen Gilliland, Carolina Möller, Anthony P. DeCaprio
Phase I and Phase II metabolic processes generally form more polar metabolites of xenobiotics and are typically a means of detoxification and preparation for excretion. Phase I metabolism, such as hydroxylation or epoxidation, refers to a number of reactions a xenobiotic may undergo where a relatively small modification occurs which may slightly increase hydrophilicity. Phase II metabolism, such as glucuronidation, refers to reactions where hydrophilicity is substantially increased by the addition of a large polar moiety. These metabolic products do not typically cause harm to the endogenous cellular components in their vicinity. However, in some cases reactive intermediates may also be formed, which may then modify nearby macromolecules to form covalent adducts, primarily through electrophilic–nucleophilic interactions (Attia, 2010; Miller & Miller, 1965). The formation of these modifications can create a potential for organ-specific toxicity (Ikehata et al., 2008; Lu et al., 2009) or, alternatively, can be innocuous. In either case, such adducts may also serve as biomarkers of exposure (Xie et al., 2013).
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