Toxication,toxification ortoxicity exaltation is the conversion of achemical compound into a more toxic form in living organisms or in substrates such assoil orwater. The conversion can be caused byenzymaticmetabolism in the organisms, as well as byabioticchemical reactions. While the parent drug is usually less active, both the parent drug and its metabolite can be chemically active and causetoxicity, leading to mutagenesis, teratogenesis, and carcinogenesis.[1][2] Different classes of enzymes, such asP450 monooxygenases,epoxide hydrolase, oracetyltransferases can catalyze the process in the cell, mostly in the liver.[2]
Parent non-toxic chemicals are generally referred to asprotoxins. While toxication is generally undesirable, in certain cases it is required for thein vivo conversion of aprodrug to a metabolite with desired pharmacological or toxicological activity.Codeine is an example of a prodrug, metabolized in the body to the active compoundsmorphine andcodeine-6-glucuronide.
Phase I ofdrug metabolism are bioactivation pathways, which are catalyzed byCYP450 enzymes, produce toxic metabolites and thus have the potential to damage cells. The unusual level of activity CYP450 enzymes might lead to the changes in drug metabolism and convert drugs into their more toxic forms. Among Phase I CYP450 enzymes, the subfamiliesCYP2D6 andCYP3A are responsible forhepatotoxicity during drug metabolism with a number of different drugs, includingflucloxacillin,troleandomycin, andtroglitazone.[3] Hepatotoxicity indicates the drug's toxicity to liver.
Paracetamol (acetaminophen, APAP) is converted into the hepatotoxic metaboliteNAPQI via thecytochrome P450 oxidase system, mainly by the subfamily CYP2E1. Hepatic reduced glutathione (GSH) will detoxify this formed NAPQI quickly if APAP is taken at a proper level. In the case of overdoses, the storage of GSH will not be enough for NAPQI detoxication, thereby resulting in acute liver injury.[4]
Oxidoreductases are enzymes that catalyze the reactions that involve the transfer of electrons.Methanol in itself is toxic due to itscentral nervous system depression properties, but it can be converted to formaldehyde by alcohol dehydrogenase and then converted to formic acid by aldehyde dehydrogenase, which are significantly more toxic.Formic acid andformaldehyde can cause severeacidosis, damage to theoptic nerve, and other life-threatening complications.[5]
Ethylene glycol (common antifreeze) can be converted into toxicglycolic acid,glyoxylic acid andoxalic acid by aldehyde dehydrogenase, lactate dehydrogenase (LDH) and glycolate oxidase in mammalian organisms.[5][6] The accumulation of the end product of the ethylene glycol mechanism,calcium oxalate, may cause malfunction in the kidney and lead to more severe consequences.[5]
Other examples of toxication by enzymatic metabolism include:
Increases in toxicity can also be caused byabioticchemical reactions. Non-living elements affect the abiotic chemical reactions. Anthropogenic trace compounds (ATCs) have potential toxicity to the organisms in aquatic system.[9]
Arsenic contamination in drinking water can be chemically toxic. The uptake and metabolism of arsenic may result in damage to the body. When organic arsenic is converted into more toxic inorganic arsenic, it causes carcinogenesis, cytotoxicity (toxic to cells) and genotoxicity (causing mutations in genes).[10]