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Liver Diseases
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
One of the major functions of the liver cell is to metabolize and eliminate drugs and other foreign compounds from the body.27,332,574 During this process, biologically or pharmacologically active substances are converted to inactive metabolites by the drug metabolizing enzyme system also termed the microsomal mixed function oxidase system.53,580 This system provides a natural protection against adverse reactions to drugs. Without these enzymes catalyzing the conversion of lipid-soluble compounds to more polar and therefore less lipid-soluble derivatives, many drugs could exert their action for an unnecessarily long time. This intrahepatic metabolism also prevents reabsorption by rendering the drugs water-soluble, allowing metabolites to be filtered through the glomerulus in the kidney. There are drugs giving rise to metabolites which remain as active as the original compounds. Occasionally, the pharmacological effect of metabolites is even greater than that of the parent compound indicating metabolic activation.
Alcohol Pharmacology and Pharmacotherapy of Alcoholism
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Aman Upaganlawar, Sindhu Ramesh, Ellery Jones, Vishnu Suppiramaniam, Timothy Moore, Muralikrishnan Dhanasekaran
This primarily consists of cytochrome P4502E1, 1A2, and 3A4 and termed as mixed function oxidase system. Microsomal ethanol-oxidizing system (MEOS) increase in chronic consumption especially CYP2E1 and with higher ethanol concentrations leading to increased rate of alcohol metabolism and elimination of other drugs metabolized by this cytochrome P450 (Lieber, 2004).
Inhibition of Colon Carcinogenesis*
Published in Herman Autrup, Gary M. Williams, Experimental Colon Carcinogenesis, 2019
Several mechanisms of inhibition of chemical carcinogenesis are possible. Antioxidants and related compounds compose one group of inhibitors. This group has the potential to scavenge reactive carcinogenic species thereby preventing active electro-philes from reaching and reacting with critical target sites. A second group of compounds can inhibit carcinogenesis by altering the microsomal mixed-function oxidase activity. This can result in either suppression of carcinogen activation or enhancement of carcinogen detoxification. The mixed-function oxidase system is important for the conversion of chemical compounds to proximate carcinogens26 as well as for the detoxification of carcinogens.27 Perhaps some compounds simply reduce the ratio of carcinogenic metabolites to detoxified metabolites to affect inhibition. A third group of inhibitors may protect against alterations in membrane structure and function (permeability and transport). As free radical scavengers, inhibitors such as selenium and vitamin E could prevent lipid peroxidation and by this mechanism preserve the membrane integrity and function. A last classification of compounds through competitive inhibition may prevent active metabolites of carcinogens from binding critical target sites as DNA. This competitive inhibition is to be distinguished from competition between the inhibitor and carcinogen for the mixed function oxidase system required for carcinogen activation.
Gastrointestinal and cardiovascular adverse events associated with NSAIDs
Published in Expert Opinion on Drug Safety, 2022
María-José Domper Arnal, Gonzalo Hijos-Mallada, Angel Lanas
NSAIDs have high lipid solubility and exhibit good bioavailability after oral, or parenteral administration. Most NSAIDs circulate in peripheral blood bound to plasma proteins. Urinary excretion of the parent drug is low due to a high binding affinity to plasma proteins [6]. Many NSAIDs have hepatic metabolism, which transform the parent drug into inactive metabolites that are eventually eliminated. The cytochrome P450 (CYP)-containing-mixed function-oxidase system is responsible for the hepatic metabolism of most NSAIDs and CYP2C9 is the most important oxidase. Allelic variations of the CYP2C9 protein (including CYP2C9 * 2 and CYP2C9 * 3) are especially relevant in the Asian population and their assessment may be relevant to optimize both the efficacy and safe use of NSAIDs in this population [2].
Genotoxicity of yellow shammah (smokeless tobacco) in murine bone marrow cells in vivo
Published in Drug and Chemical Toxicology, 2021
Saeed Alshahrani, Pankaj Tripathi, Hassan A. Alhazmi, Syed Mamoon Hussain, Abdul Hakeem Siddiqui, Waquar Ahsan, Mohammad Al Bratty
CP (covalent DNA-binding agent) was used as a positive control chemical in this study (OECD 2013). In the present investigation, induction of higher percentages of aberrant metaphases, CAs (excluding gaps), mitotic depression, micronucleated cells per thousand PCEs in mouse bone marrow, and cytotoxicity by CP (40 mg/kg b.w. of mice), were in thorough accordance with its earlier reported clastogenicity (Shokrzadeh et al. 2013). Genotoxicity of CP is based on the requirement of its metabolic activation which could be a probable mechanism for this effect. Apparently, the cytochrome P450 mixed function oxidase system causes the hepatic metabolism of CP, resulting in the production of active metabolites, phosphoramide mustard and acrolein, which are responsible for free radical generation, DNA damage and antineoplastic effects of CP (Habibi et al. 2015, Tripathi et al. 2013a).
Vitamin D Resists Cyclophosphamide-Induced Genomic and DNA Damage in CHL Cells In Vitro and in Mice In Vivo
Published in Nutrition and Cancer, 2019
Huaqing Liu, Xiaoqing Feng, Shuiyan Wu, Tianzhou Zong, Bingyan Li, Zengli Zhang
To observe the protective effects on CP-induced genomic instability, treatments using 10, 20, 50, and 100 nM 1α,25-(OH)2D3 were compared to an ethanol vehicle. 1α,25-(OH)2D3 treatment was performed before and/or concomitantly with exposure to CP. CP is an alkylating agent and shows activity after conversion by mixed function oxidases in the liver (19). In this in vitro assay, a hepatic microsomal mixed function oxidase system (S9 mixed-function system, containing 0.125 ml of S9, 0.02 ml of 0.4 M MgC12, 0.02 ml of 1.65 M KCl, 1.791 mg of glucose-6-phosphate, 3.0615 mg of coenzyme II in 1640-medium complement to a final volume of 1 ml) was added to convert CP to active metabolites. CHL cells were plated in cell culture plates or on cover slips at a density of 5 × 105 cells/well in the presence of different 1α,25-(OH)2D3 dose, cultured 24 h. Then, CP at final concentration 50 μg/ml and S9 mixed-function system were added at the same time, cultured 6 h. CP and 1α,25-(OH)2D3 no-treated group was set as blank control.