Xenobiotics, metabolism conjugation

B. Ketterer, The Role of Nonenzymatic Reactions of Glutathione in Xenobiotic Metabolism , Drug Metab. Rev. 1982, 13, 161 - 187 B. Ketterer, G. J. Mulder, Glutathione Conjugation , in Conjugations Reactions in Drug Metabolism , Ed. G. J. Mulder, Taylor and Francis, London, 1990, p. 307 - 364. 

With some of the phase 2 metabolizing enzymes, there may be strict ontogenetic patterns of expression. Sulfate conjugation ability occurs early in rats, whereas glucuronidation (of xenobiotics), and conjugation with glutathione and amino acids, only develop over about 30 days from birth. 

Caldwell J. Conjugation mechanisms of xenobiotic metabolism Mammalian aspects. In Paulson GD, Caldwell J, Hutton DH, et ah, eds. Xenobiotic Conjugation Chemistry. Washington American Chemical Society, 1986. 

Some metabolic conjugative processes result in the production of lipophilic derivatives that are not readily eliminated. While their physical properties are different from the classical hydrophilic conjugates, the mechanism of formation clearly defines them as conjugates (i.e., they are formed as the result of a union of xenobiotic metabolites with endogenous molecules). The reactions involve the coupling of xenobiotic acids and alcohols with endogenous intermediates of lipid synthesis (i. e., the acids with glycerol and cholesterol and the alcohols with the fatty acids). 

Xenobiotics are biotransformed by phase I enzymes and phase II conjugation reactions to form a variety of metabolites that are generally more water-soluble and less toxic than the parent compound. Occasionally, the enzymic action of phase I or II systems leads to the formation of unstable intermediates or reactive metabolites that are toxic or carcinogenic. Many physiological factors influence the rate of xenobiotic metabolism and the relative importance of different pathways of metabolic activation or detoxication. 

In addition to DNA adducts that occur as a result of covalent binding of reactive intermediates generated by oxidation or conjugation of parent compounds to DNA, reactive oxygen species produced during xenobiotic metabolism can also react with nucleophilic biomolecules. 

Bakke JE (1989) Metabolites derived from glutathione conjugation. In Hutson DH, Caldwell J, Paulson GD (eds) Intermediary Xenobiotic Metabolism in Animals. Taylor. Francis, London, p 205... 

The liver is the principal organ responsible for xenobiotic metabolism. One of its major roles is to convert lipophilic nonpolar molecules to more polar water-soluble forms. The drug molecule (a xenobiotic) can be modified by phase I reactions, which alter chemical structure by oxidation, reduction, or hydrolysis or by phase II reactions, which conjugate the drug (glucuronidation or sulfation) to create more water-soluble forms. Typically, both phase I and phase II reactions occur. Most drug metaboHsm takes place in the microsomal fraction of the hepatocytes, where many environmental chemicals and endogenous biochemicals (xeno-biotics) are also processed by the same mechanisms. 

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