Toxication

Toxication is the process of metabolism in which the metabolite of a compound is more toxic than the parent drug or chemical.

Toxication may involve:

• Changing the physicochemical properties to cause a change in the microenvironment
• Increasing the potency of a compound
• Conversion of the compound into:
  • Electrophile
  • Free radical
  • Nucleophile
  • Redox-active reactant

Toxication (in the context of Biodegration) consists of 3 steps:

• STEP 1: Hydrodesulfurization
• STEP 2: Hydrolysis
• STEP 3: Sulfotransferase

While toxication is generally undesirable, in certain cases it is required for the in vivo conversion of a prodrug or chemical to a metabolite with desired pharmacological or toxicological activity. Codeine is an example of a prodrug, which is metabolized in the body to the opioid known as morphine.

Examples

The breakdown of methanol in the mammalian liver. Methanol in itself is toxic due to its CNS depressant properties, but acquires more dangerous toxicity through its metabolites formic acid and formaldehyde, which can cause severe acidosis, damage to the optic nerve, and other life-threatening complications.

The metabolism of paracetamol (acetaminophen) to the hepatotoxic metabolite NAPQI via the cytochrome P450 oxidase system.

Metabolic Activation of N-Hydroxy-2-aminofluorene and N-Hydroxy-2-acetylaminofluorene by Monomorphic N-Acetyltransferase (NAT1) and Polymorphic N-Acetyltransferase (NAT2) Metabolic Activation of N-Hydroxy-2-aminofluorene and N-Hydroxy-2-acetylaminofluorene by Monomorphic N-Acetyltransferase (NAT1) and Polymorphic N-Acetyltransferase (NAT2) in Colon Cytosols of Syrian Hamsters Congenic at the NAT2 Locus - Hein et al. 53 (3): 509 - Cancer Research

Role of cytochrome P4501B1 in benzo[a]pyrene bio-activation to DNA-binding metabolites Evidence from 32p-postlabeling for formation of 3-hydroxybenzo[a]pyrene and benzo[a]pyrene-3,6-quinone as major proximate genotoxic intermediates Role of cytochrome P4501B1 in benzo[a]pyrene bio-activation to DNA-binding metabolites in mouse vascular smooth muscle cells: Evidence from 32p-postlabeling for formation of 3-hydroxybenzo[a]pyrene and benzo[a]pyrene-3,6-quinone as major proximate genotoxic intermediates - Moorthy et al., 10.1124/jpet.102.044271 - Journal of Pharmacology And Experimental Therapeutics

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