Veterinary Taxicology

BIOTRANSFORMATION

• A few substances are excreted unchanged. But a majority of substances undergo biotransformation or metabolism. These reactions are normally known as detoxification reactions. But this may not be true always.
• Some agents that are non-toxic by themselves are converted into toxic metabolites and this is known as lethal synthesis.
• Parathion is a biologically inert organophosphorous compound while its metabolite paraoxon is a cholinesterase inhibitor.
• Fluoroacetate and fluoroacetamide are converted into fluorocitrate. This fluorocitrate inhibits the action of the enzyme aconitase that catalyses the isomerization of citrate to isocitrate, thus blocking the tricarboxylic or Kreb’s cycle and producing intoxication.
• As in the case of pharmacokinetics, biotransformation in toxicokinetics also includes phase I and phase II reactions.
• A foreign compound is seldom exclusively metabolized along a single pathway and although one may predominate, a given animal species often produces a number of different metabolites from a single foreign compound.
• Interspecies differences in the capacity to metabolize foreign compounds can result in a much greater susceptibility to poisoning by certain materials in some animals. For example, benzoic acid preserved pet food can be toxic to cats, as they have poorly developed glucuronic acid conjugating capacity.
• In some cases, the increased tolerance to subsequent exposures of a toxicant is due to enzyme induction initiated by the previous exposure.
• Biotransformation of xenobiotics occurs in two phases.
  • In the first phase, metabolites containing hydroxyl, carboxyl and amino groups are produced. These are polar in nature. They may be excreted in urine without being subjected to conjugation reactions.
  • The second phase involves conjugation reactions like glucuronic acid conjugation, sulfation, acetylation, glutathione conjugation, methylation and amino acid conjugation.
• The most common first phase reactions are oxidative reactions involving hydroxylation (acetanilide to paracetamol), deamination (amphetamine to benzoic acid) or dealkylation (codeine to morphine) of foreign compounds.
• Products of biotransformation are occasionally unstable and decompose to release reactive compounds as free radicals, strong electrophiles or epoxides.
• Epoxides have a strong electrophilic character and are generally unstable and react with nucleophilic groups in macromolecules such as proteins, DNA and RNA. This may result in faulty replication, transcription and synthesis of abnormal proteins leading to mutation and carcinogenesis.