Toxication
A number of xenobiotics (e.g., strong acids and bases, nicotine, aminoglycosides, ethylene oxide, methylisocyanate, heavy-metal ions, HCN, CO) are directly toxic.
Whereas the toxicity of others is due largely to metabolites.
Biotransformation to harmful products is called toxication or metabolic activation.
For example, oxalic acid formed from ethylene glycol may cause acidosis and hypocalcemia as well as obstruction of renal tubules by precipitation as calcium oxalate.
Occasionally, chemicals acquire structural features and reactivity by biotransformation that allows for a more efficient interaction with specific receptors or enzymes.
For example, the organophosphate insecticide parathion is bio transformed to paraoxon, an active cholinesterase inhibitor.
The rodenticide fluoroacetate is converted in the citric acid cycle to fluoroacetate, a false substrate that inhibits aconitase
The general anesthetic methoxyflurane releases fluoride ion which inhibits several enzymes (including enolase in the glycolytic pathway)
And which contributes to renal injury after prolonged anesthesia.
This increased reactivity may be due to conversion into
(1) electrophiles,
(2) free radicals,
(3) nucleophiles, or
(4) redox-active reactants.
Detoxication
Biotransformation that eliminates an ultimate toxicant or prevents its formation is called detoxication.
Detoxication can take several pathways, depending on the chemical nature of the toxic substance.
Types of Detoxication
Alcohol detoxication
Alcohol detoxification is a process by which a heavy drinker’s system is brought back to normal after being habituated to having alcohol in the body continuously for an extended period of substance abuse.
Serious alcohol addiction results in a down regulation of GABA neurotransmitter receptors.
Metabolic detoxication
Often drug detoxification and treatment will occur in a community program that lasts several months and takes place in a residential setting rather than in a medical center.
Alternative medicine
Certain approaches in alternative medicine claim to remove “toxins” from the body through herbal, electrical or electromagnetic treatments.
These toxins are undefined and have no scientific basis, making the validity of such techniques questionable.
Detoxication of Toxicants with No Functional Groups
In general, chemicals without functional groups, such as benzene and toluene, are detoxicated in two phases.
Initially, a functional group such as hydroxyl or carboxyl is introduced into the molecule, most often by cytochrome-P450 enzymes.
Subsequently, an endogenous acid, such as glucuronic acid, sulfuric acid, or an amino acid, is added to the functional group by a transfer.
Detoxication by Enzymes
An alternative mechanism for the elimination of thiols, amines, and hydrazine’s is oxidation by flavin-containing monooxygenases.
Some alcohols, such as ethanol, are detoxicated by oxidation to carboxylic acids by alcohol and aldehyde dehydrogenases.
A specific detoxication mechanism is the biotransformation of cyanide to thiocyanate by rhodanese or mercaptan pyruvate sulfur transferase.
Detoxication of Electrophiles
A general mechanism for the detoxication of electrophilic toxicants is conjugation with the thiol nucleophile glutathione.
This reaction may occur spontaneously or can be facilitated by glutathione S-transferases.
Metal ions such as Ag+, Cd2+, Hg2+, and CH3Hg+ ions readily react with and are detoxicated by glutathione.
Detoxication of Free Radicals
Because O2¯• can be converted into much more reactive compounds, its elimination is an important detoxication mechanism. This is carried out by superoxide dismutase’s (SOD), high-capacity enzymes located in the cytosol (Cu, Zn-SOD) and the mitochondria (Mn-SOD), which convert O2¯• to HOOH.
Detoxication of Protein Toxins
Presumably, extra- and intracellular proteases are involved in the inactivation of toxic polypeptides.
Several toxins found in venoms, such as α– and β-bungarotoxin, erabutoxin, and phospholipase, contain intramolecular disulfide bonds that are required for their activity.
These proteins are inactivated by thioredoxin, an endogenous dithiol protein that reduces the essential disulfide bond.