Cytochrome P450-Dependent Metabolism of Drugs and Carcinogens in Skin
Rhoda G. M. Wang, James B. Knaak, Howard I. Maibach in Health Risk Assessment, 2017
The enzymes which metabolize foreign compounds including drugs and other xenobiotics are known as drug metabolizing enzymes. They were first discovered in liver, but thereafter virtually all extrahepatic tissues including skin1-8 have been shown to possess varying levels of such activity. The drug and xenobiotic metabolism is a general phenomenon which plays a major role in the removal of foreign compounds from the body. The major role of such enzymes is to convert lipid-soluble foreign chemicals into water-soluble metabolites which can be eliminated easily from the body. This enzyme system therefore diminishes the biologic activity of foreign compounds. Ironically, this enzymatic process also generates chemically reactive metabolites which can covalently bind to cellular macromolecules such as DNA and thereby result in cell toxicity, mutagenicity, and often cancer induction.9
Gastrointestinal Function and Toxicology in Canines
Shayne C. Gad in Toxicology of the Gastrointestinal Tract, 2018
Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems [29–34,123,136,148,202,230,236,263,273,286,296,301,316,364,410]. More generally, xenobiotic metabolism (from the Greek xenos, “stranger” and biotic, “related to living beings”) is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organism’s normal biochemistry, such any drug or poison. These pathways are a form of biotransformation present in all major groups of organisms and are considered to be of ancient origin. These reactions often act to detoxify poisonous compounds (although in some cases the intermediates in xenobiotic metabolism can themselves cause toxic effects). The study of drug metabolism is called pharmacokinetics.
Ovotoxic Environmental Chemicals: Indirect Endocrine Disruptors
Rajesh K. Naz in Endocrine Disruptors, 2004
Phase I enzymes, including the cytochrome P450 enzymes, often generate activated metabolites of xenobiotics, and Phase II classes of enzymes generally cause detoxification during xenobiotic metabolism. This formation of non-toxic metabolites usually also enhances their solubility for excretion. Major enzymatic pathways for detoxification of xenobiotic epoxides are hydration to corresponding diols (catalyzed by microsomal epoxide hydrolase, EH), and conjugation with glutathione (catalyzed by glutathione-S-transferase, GST). Detoxification reactions catalyzed by EH and GST occur in many tissues including the ovary.[114,117] Expression of the specific isoforms of GSTs in rat ovaries was found to be age-dependent and hormonally regulated.[118] In human ovaries, specific isoenzymes were regionally compartmentalized.[119] Activities of EH, GST, and P450s in rats were high in the neonate, decreased by 2 weeks of age, reached a maximum near the onset of puberty, and were even further elevated in pregnant rats.[114] These data are suggestive of hormonal induction of ovarian detoxification enzymes.
A transcriptional regulatory network of HNF4α and HNF1α involved in human diseases and drug metabolism
Published in Drug Metabolism Reviews, 2022
Jianxin Yang, Xue Bai, Guiqin Liu, Xiangyang Li
Detoxification and drug metabolism of xenobiotics occur mainly in the liver in two stages. The first stage is oxidation, reduction, and hydrolysis by phase I DMEs cytochrome P450 (CYP450) and a small number of flavin-containing monooxygenases (FMO). The second stage is carried out by phase II DMEs glutathione-S-transferase (GST), UDP-glucuronyltransferase (UGT), and sulfotransferase (SULT) for the conjugation reaction. In addition, some DTs participate in the excretion of drugs and their metabolites. The expression of DMEs and DTs in many tissues and organs determines drug distribution in the body and the resulting pharmacological and toxicological effects. Interindividual differences in drug response are generally related to changes in the expression levels of drug disposition genes, and control of the expression of these genes involves the binding of TFs to upstream regulatory promoter sequences.
Chemopreventive role of arabinogalactan against experimentally induced pulmonary carcinogenesis: a study in relation to its initiation phase
Published in Drug and Chemical Toxicology, 2021
Ashwani Koul, Shaffy Garg, Vandana Mohan
Among the detoxifying mechanisms of xenobiotic metabolism, a key role is played by GST, a component of phase II enzymes that functions primarily in conjugating ‘functionalized P450 metabolite’ with endogenous ligands (GSH) rendering them suitable for elimination from the body (Singh et al.2006). In present study, the activities of the phase II enzyme were significantly decreased in B(a)P-induced animals, which denote that tissue were more susceptible to carcinogenic effect of B(a)P. There is strong evidence to suggest a relationship between the depletion of GST and an increase in cancer susceptibility (Hosgood et al.2007). The observed concomitant increase in GST activity upon AG administration in B(a)P treated animals depicts the role of AG in increasing the ability of the cells to detoxify activated metabolic compounds of B(a)P by upregulating the activity of GST. An earlier investigation also supports our observation which showed that supplementation of water-soluble polysaccharide from Antrodia cinnamomea significantly elevated the GST activity in submerged cultured liver cells (Tsai et al.2007). It is evident from the present findings that AG acts as bifunctional enzyme inducer as it induces both phase I and II enzyme systems at different time intervals during the initiation of carcinogenesis. This reinforces the balance of xenobiotic metabolism towards detoxification and therefore, might be attributed to playing a major role in cytoprotection and chemoprevention.
Cannabinoids and drug metabolizing enzymes: potential for drug-drug interactions and implications for drug safety and efficacy
Published in Expert Review of Clinical Pharmacology, 2022
Keti Bardhi, Shelby Coates, Christy J.W. Watson, Philip Lazarus
There are 10 major CYP enzymes involved in xenobiotic drug metabolism: CYP3A4, CYP2A6, CYP2D6, CYP2C8, CYP2C9, CYP1A2, CYP2C19, CYP2E1, CYP2B6, and CYP2A6, and these account for 70–80% of all drug metabolism [143]. CYP-mediated metabolism is highly susceptible to DDI and is thought to account for much of the variability in drug response [143,144]. As the risk for DDI is high for the CYP family of enzymes, the FDA has proposed a set of guidelines for the study of the interactions between CYPs and potential perpetrator drugs [145]. This guidance focuses both on the inhibition and induction of CYP enzymes in an in vitro system, and also tasks researchers with the characterization of the DDI potential of metabolites, if they exceed parent drug exposure by 1.25-fold [145]. As several THC and CBD metabolites exceed parent drug exposure by ≥ 1.25-fold, this becomes particularly important when considering the potential inhibitory effects of cannabis. The FDA recommends not only in vitro DDI studies but also static (mechanistic static modeling) and dynamic (physiologically based pharmacokinetic – PBPK) modeling when preliminary data and physiological conditions suggests a potential interaction [145].
Related Knowledge Centers
- Biotransformation
- Enzyme
- Metabolic Pathway
- Xenobiotic
- Pharmacokinetics
- Metabolism
- Drug
- Reaction Intermediate
- Medication
- Pharmacology