Explore chapters and articles related to this topic
Pharmacokinetic Interactions of Drinking Water Contaminants
Published in Rhoda G.M. Wang, Water Contamination and Health, 2020
Ronald Brown, Jerry N. Blancato, David Young
Although we often refer to cytochrome P450 as a single enzyme, over 30 forms or isozymes of this enzyme exist in many species, including humans (44). Each of these forms exhibits some degree of substrate specificity. For example, cytochrome P450 2E1 is largely responsible for catalyzing the oxidation of a number of important drinking water contaminants, such as benzene, chloroform, carbon tetrachloride, and methylene chloride, as well as ethanol and such drugs as acetaminophen (Table 5). The substrate specificity of other P450 isozymes is also well known (45). Clearly, knowledge of the isozyme that serves as the primary catalyst of a compound is important in determining whether another compound also metabolized by the same isozyme is likely to serve as a competitive inhibitor of the metabolism of the compound of interest. Many of the inhibited reactions listed in Table 4 are the result of competitive inhibition between two P450 2E1 substrates. In addition, a number of preferential inhibitors of specific P450 isozymes are known to exist. For example, disulfuram serves as a mechanism-based inhibitor selective for P450 2E1. Knowledge of the selectivity of this inhibitor not only gives investigators the ability to use disulfuram as an isozyme-specific inhibitor of P450 2E1 but also enables risk assessors to predict that patients taking disulfuram clinically may be less able to metabolize the compounds listed in Table 5.
Toxic Responses of the Liver
Published in Stephen K. Hall, Joana Chakraborty, Randall J. Ruch, Chemical Exposure and Toxic Responses, 2020
The liver is the principle organ for the detoxification of ingested, inhaled, or absorbed toxic chemicals. Usually metabolism results in the generation of less toxic products that are excreted in the bile or urine. However, some chemicals enter the liver as relatively nontoxic entities but are metabolized to potent hepatotoxic products. This process of the metabolic conversion of a nontoxic agent into a toxic one is known as biotransformation. The vast majority of hepatotoxic compounds require biotransformation before they are toxic. Usually biotransformation is mediated by the cytochrome P450 mixed function oxidase enzymes. As discussed in other chapters, the cytochrome P450 enzyme family is large, with more than 150 members or isoenzymes. Individual isoenzymes may have broad specificity and are able to metabolize many substances whereas others have more narrow specificity and metabolize only one or a few substrates. This multienzyme cytochrome P450 system probably evolved in response to the many toxic chemicals in the prehistoric environment and diets. The toxic products of biotransformation include electrophilic derivatives of the parent compound which bind to nucleophilic protein (e.g., acetaminophen) or DNA (e.g., benzo(a)pyrene) and free radicals which degrade macromolecules such as lipids and proteins (e.g., carbon tetrachloride and bromobenzene).
Precision Medicine
Published in Paul Cerrato, John Halamka, Reinventing Clinical Decision Support, 2020
The cytochrome P-450 family of liver enzymes is responsible for metabolizing many drugs, and mutations to the genes that control the synthesis of these enzymes can have a significant impact on how an individual responds to drugs that are broken down by these enzymes. Such genetic variants can result in a patient becoming a slow metabolizer, in which case the drug will have a prolonged therapeutic effect, risking toxicity, or a fast metabolizer, in which case a patient may experience a sub-therapeutic effect from said drug.
Molecular modeling strategy to design novel anticancer agents against UACC-62 and UACC-257 melanoma cell lines
Published in Egyptian Journal of Basic and Applied Sciences, 2023
Abdullahi Bello Umar, Adamu Uzairu
The metabolism describes the biochemical transformation of a drug candidate by the body. Thus, drugs usually produce several metabolites, which might have different pharmacological and physicochemical properties. It is necessary to consider the metabolism of the drugs, and drug–drug interactions [46]. The Cytochrome P450 (CYP450) plays a vital role in drug metabolism because it is the main liver protein system involved in oxidation (phase-1 metabolism), as in the case of this research. To date, only 17 CYP families were identified in humans, even though only (CYP1, CYP2, CYP3 and CYP4, respectively) are involved in the drug metabolism, with a CYP (1A2, 2C9, 2C19, 2D6 and 3A4, respectively) were identified to be responsible for the biotransformation of more than 90% of the drugs that undergo phase-I metabolism [46,47]. Additionally, cytochrome CYP3A4 inhibition is the most vital phenomenon in this research [48]. The results presented in Table 4 indicated that molecules DMB1, BSN1, BSN2 and BSN3 are the substrates of CYP3A4 and the inhibitors of CYP3A4, respectively.
In vitro functional analysis of human cytochrome P450 2A13 genetic variants: P450 2A13*2, *3, *4, and *10
Published in Journal of Toxicology and Environmental Health, Part A, 2018
Vitchan Kim, Sora Yeom, Yejin Lee, Hyoung-Goo Park, Myung-A Cho, Harim Kim, Donghak Kim
Human cytochromes P450 (P450) are responsible for metabolism of therapeutic drugs and bioactivation of many carcinogens (Ginsberg et al. 2017; Guengerich 2008). In particular, the P450 1A, 1B, 2A subfamilies, as well as P450 3A4 are known to play critical roles in bioactivation of chemicals (Shimada 2017; Shimada, et al. 2016a). There are three enzymes (2A6, 2A7, and 2A13) in the P450 2A subfamily in the human genome. P450 2A6 has been intensively studied with respect to drug metabolism as it is expressed in the human liver (Guengerich 2015; Han et al. 2012; Lee and Kim 2011). The expression of the functional P450 2A7 is still not clear and data regarding P450 2A7 catalytic activity remain to be determined (Guengerich 2015). P450 2A13 expressed predominantly in human trachea and lung (Shimada, et al. 2016b; Guengerich 2015) exhibits 94.5% protein sequence homology with P450 2A6 (Kumondai et al. 2018; Su et al. 2000; Von Weymarn, Retzlaff, and Murphy 2012). Since P450 2A6 is present in human lung at lower levels, P450 2A13 in pulmonary tissue is considered as the primary enzyme that activates nicotine-derived procarcinogens into DNA-altering compounds that induce lung cancer development (Huang et al. 2017; Smith et al. 2007). P450 2A13 might oxidize some drugs, but there is no apparent evidence that this enzyme makes a major contribution to the clearance of any compounds (Guengerich 2015).
Exposure to organic solvents and hepatotoxicity
Published in Journal of Environmental Science and Health, Part A, 2020
Cristiano Brauner, Dvora Joveleviths, Mário R. Álvares-da-Silva, Norma Marroni, Silvia Bona, Elizângela Schemitt, Raissa Nardi
These results confirm that one should be careful when classifying solvents such as toluene as low risk, especially if there is high and continued exposure to solvent mixtures, due to the additive effect. Even removing confounding factors such as alcoholism and obesity, aromatic solvents may cause hepatotoxicity, with consequences that are not yet fully known. It is also necessary to consider the individual susceptibility and the particularities of the metabolism of toxic substances in each individual through cytochrome P450, which can be greatly influenced by genetic and environmental factors. [42]