Bioactivation and Tissue Toxicity

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Chapter: Biopharmaceutics and Pharmacokinetics : Biotransformation of Drugs

Formation of highly reactive metabolites (from relatively inert chemical compounds) which interact with the tissues to precipitate one or more of the several forms of toxicities such as carcinogenesis and teratogenesis is called as bioactivation or toxicological activation.


BIOACTIVATION AND TISSUE TOXICITY

Formation of highly reactive metabolites (from relatively inert chemical compounds) which interact with the tissues to precipitate one or more of the several forms of toxicities such as carcinogenesis and teratogenesis is called as bioactivation or toxicological activation. The reactive, chemically unstable species, capable of toxication, are broadly divided into two categories (see Fig. 5.4.) —

·            Electrophiles

·            Free radicals.


Fig. 5.4. Mechanisms of tissue toxicity by bioactivation of drugs

Electrophiles are species deficient in electron pair. The enzyme system through which they are generated is cytochrome P-450. Carbon, nitrogen or sulphur-containing compounds can be metabolically activated to yield electrophiles. Important electrophiles are epoxides (e.g. epoxide of benzo(a)pyrene present in cigarette smoke which causes cancer), hydroxylamines, nitroso and azoxy derivatives, nitrenium ions and elemental sulphur. The mechanism by which electrophiles precipitate toxicity is through covalent binding to nucleophilic tissue components such as macromolecules (proteins, nucleic acids and lipids) or low molecular weight cellular constituents. Covalent binding to DNA is responsible for carcinogenicity and tumour formation. The body’s defence against electrophiles is their inactivation by conjugation with glutathione, the most abundant cellular nucleophile with -SH group. An example of tissue toxicity due to electrophiles is hepatotoxicity of paracetamol metabolites.


Free Radicals: are species containing an odd number of electrons. They may be positively charged (cation radical), negatively charged (anion radical) or neutral (neutral radical).


Free radicals are generally formed via NADPH cytochrome P-450 reductase or other flavin containing reductases. Xenobiotics that on metabolic activation yield free radicals are quinones, arylamines, nitroaryls and carbon tetrachloride. Endogenous compounds such as epinephrine and DOPA can also generate free radicals. Most free radicals are organic. They produce toxicity by peroxidation of cellular components. An important class of free radicals is inorganic free radicals such as hydrogen peroxide (H2O2) and superoxide anion (O2-).

These oxidative moieties can cause tremendous tissue damage leading to mutations or cancer. The potential toxicity of free radicals is far greater than that of the electrophiles. Cellular defence mechanisms against free radicals include control imposed by membrane structure, neutralization by glutathione, control exerted by non-enzymatic antioxidant scavengers such as vitamins A, E and C and enzymatic inactivation of oxygen derived free radicals.

Generation of reactive metabolites is indicated by modification in enzyme activities, formation of glutathione conjugates (or mercapturic acids) and depletion in tissue levels of glutathione. Since the availability of glutathione in the body determine the threshold for toxic response, thiols (e.g. N-acetyl cysteine) can be used to treat poisoning by drugs such as paracetamol that yield reactive metabolites.

Table 5.7 lists some of the compounds whose metabolites are tissue reactive.

TABLE 5.7

Compounds and their Metabolic Reaction that Generate Toxic Intermediates



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