Current Drug Metabolism - Volume 22, Issue 8, 2021

Polycyclic aromatic hydrocarbons (PAHs) represent a class of widely distributed environmental pollutants that have been primarily studied as genotoxic compounds. Their mutagenicity/genotoxicity largely depends on their oxidative metabolism leading to the production of dihydrodiol epoxide metabolites, as well as additional metabolites contributing to oxidative DNA damage, such as PAH quinones. However, both parental PAHs and their metabolites, including PAH quinones or hydroxylated PAHs, have been shown to produce various types of non-genotoxic effects. These include e.g., activation of the aryl hydrocarbon receptor and/or additional nuclear receptors, activation of membrane receptors, including tyrosine kinases and G-protein coupled receptors, or activation of intracellular signaling pathways, such as mitogen-activated protein kinases, Akt kinase and Ca²⁺-dependent signaling. These pathways may, together with the cellular DNA damage responses, modulate cell proliferation, cell survival or cell-to-cell communication, thus contributing to the known carcinogenic effects of PAHs. In the present review, we summarize some of the known non-genotoxic effects of PAHs, focusing primarily on those that have also been shown to be modulated by PAH metabolites. Despite the limitations of the available data, it seems evident that more attention should be paid to the discrimination between the potential non-genotoxic effects of parental PAHs and those of their metabolites. This may provide further insight into the mechanisms of toxicity of this large and diverse group of environmental pollutants.

Background: The variability in drug response is highly complex and can be attributed to the polymedication, genetic polymorphisms modulating drug-metabolizing enzyme activities (cytochromes P450, CYP), physiological and environmental factors.” sentence could be revised as “The variability in drug response is highly complex and can be attributed to the polymedication, genetic polymorphisms modulating drugmetabolizing enzyme activities (cytochromeP450s (CYP)), physiological and environmental factors. Objective: The main objective of this review is to deeply discuss the role of biotransformation in the occurrence of antidepressant and anticonvulsant induced inter individual variabilities with the focus on genetic variations and drug interactions. Methods: An extensive search of the literature has been conducted related to biotransformation of the antidepressant and anticonvulsant agents on relationships between genetic differences and drug interactions on available databases. Following keywords are used for relevant articles: “metabolic enzyme”, “pharmacokinetic”, “antidepressant”, “anticonvulsant”, “genetic variations”, “enzyme inhibition”, “enzyme induction” and also with a list of all included antidepressant and anticonvulsants. Results: In the present review, we provided an overview of documented clinically significant pharmacokinetic drug interactions, physiological and environmental differences. We further discuss the significance of genetic variations in drug metabolizing enzymes to underline the need for using the information on both genotype and drug interactions towards implementing better clinical outcomes through personalized medicine in neurology and psychiatry. Conclusion: The present review clearly illustrates that interindividual differences in the biotransformation (including genetic variability of the drug metabolizing enzymes, age, sex, diet) of the antidepressant and anticonvulsant drugs, which are commonly prescribed medications globally, has a crucial role in the occurrence of adverse effects and various drug responses. Therefore, the potential results of the drug-drug interactions and individual genetic characteristics should always be considered to make pharmacotherapy safer and more effective, as they have major clinical implications.

An “endocrine disruptor” has been broadly defined as an exogenous chemical that interferes with the production, release, transportation, metabolism, binding, action, or the elimination of endogenous hormones, which are responsible for homeostasis, reproduction, development or behaviour. Diverse groups of chemicals such as pharmaceuticals, phytoestrogens, natural hormones, and synthetic chemicals such as pesticides, plasticizers, phthalates, parabens, polychlorinated/polybrominated biphenyls, bisphenols are shown to interfere with the endocrine system, and they have been defined as EDs in the last three decades. As for all chemicals, the biotransformation of EDs has a decisive role in their potential toxic effects. Humans are exposed to vast amounts of diverse chemicals throughout their lives. Fortunately, most of the chemicals are converted via biotransformation reactions catalyzed by the enzymes, into more hydrophilic metabolites, which are readily excreted in urine or bile. Biotransformation reactions resulting in less toxic metabolites are known as detoxification. However, some biotransformation reactions are called bioactivation, in which more toxic metabolites are formed. In the case of EDs, metabolites formed via bioactivation usually have a higher affinity for a hormone receptor or induce/inhibit an enzyme involved in the synthesis or catabolism of an endogenous hormone more dramatically compared to their parent compound. In the present review, the role of bioactivation in endocrine modulating effects of chemicals from all groups of EDs, namely endogenous estrogens, phytoestrogens, synthetic/industrial chemicals, and pharmaceuticals it can be were discussed.

Chloro-s-triazines-atrazine, cyanazine, propazine, simazine, and terbuthylazine-are structurally similar herbicides, differing only in specific s-triazine4-and 6-N alkyl substituents. It is generally regarded that their toxicokinetics, such as, metabolic pathways, biological effects and toxicities, also share more similar features than the differences. Consequently, it is useful to compare their characteristics to potentially find useful structure-activity relationships or other similarities or differences regarding different active compounds, their metabolites, and biological effects including toxic outcomes. The ultimate goal of these exercises is to apply the summarized knowledge-as far as it is possible regarding a patchy and often inadequate database-to cross the in vitro-in vivo and animal-human borders and integrate the available data to enhance toxicological risk assessment for the benefit of humans and ecosystems.

In vivo biotransformation of exposed chemicals is one of the major factors that determine the concentration and the duration of a substance at the systemic site of effect. Given that toxicity is expressed as a function of two factors, namely dose and time, the type and intensity of the toxicity are directly dependent on the chemical transformation of the exposed parent substance. This dependency involves two different situations. The amount of the chemical reaching the target will be decreased with the extent of metabolism if the parent chemical is toxic, and the opposite is true if the metabolite(s) is toxic instead. To date, the liver microsomal fraction in mammals has been justifiably considered as the center of biotransformation reactions because the liver and microsomes (i.e., endoplasmic reticulum component of the cell) possess the most abundant types and quantities of xenobiotic-metabolizing enzymes, especially the cytochrome P450 supergene enzyme family. These enzymes are common in all kingdoms of life, which strongly suggests that the origin of life is common. It is already known that various drugs enter mitochondria by different mechanisms, and this translocation is believed to be responsible for mitochondrial effects that are part of the therapeutic actions of various drugs such as lipid-lowering statins or antidiabetogenic thiazolidindiones. However, the discovery of mitochondrial forms of the xenobiotic-metabolizing enzymes provoked discussions about whether mitochondria metabolize drugs and other chemicals to some extent. This possibility may particularly be important as mitochondria have various critical cellular structures and functions. In the case of in situ generated metabolite(s), when there are adverse interactions with either these structures or functions, various toxic outcomes may appear. In this review, we compiled studies in the literature regarding biotransformation of drugs and other chemicals catalyzed by mitochondria where it is both an initiator and target of toxicity.