Metabolic activation, conjugation reactions

The second phase of metabolism consists of synthetic reactions that convert active compounds into inactive excretory products. Drugs that contain suitable chemical groups, such as —OH, —NHa, or —COOH, can undergo these synthetic conjugation reactions if not present in the parent compound, such drugs may be introduced during phase one reactions. Phase one and phase two metabolic reactions occur sequentially. 

Reichert D, Schutz S, Metzler M. 1985. Excretion pattern and metabolism of hexachlorobutadiene in the rats Evidence for metabolic activation by conjugation reactions. Biochem Pharmacol 34 499-505. 

Phase III reactions occur primarily in plants presumably because excretion of Phase II conjugates is Insignificant in plants. Phase III reactions are mechanisms whereby plants can reduce the effective concentration of xenobiotlc compounds in the cytoplasm. Thus, conjugation reactions provide mechanisms for the elimination of xenobiotlc compounds from sites of continuing metabolic activity in all organisms ( ) ... 

Some drugs that are not candidates for active tubular secretion may be metabolized to compounds that are. This is often true for metabolites that are formed as a result of conjugative reactions. Because the conjugates are generally not pharmacologically active, increases in their rate of elimination through active secretion usually have little effect on the drug s overall duration of action. 

DETOXIFICATION Hie metabolic conversion of a substance into another substance of lower toxicity the mammalian liver is an important site of detoxification processes, among which are monooxygenase reactions and conjugations. (See also METABOLIC ACTIVATION and TOXIFICATION)... 

Different enzymatic reactions that occur during the metabolism of chemicals have been well categorized. The biotransformation and conjugation reactions may lead to either the detoxication of the toxicant and the excretion of its metabolites, or to the activation of the toxicant into more reactive intermediates. These may, in turn, react with glutathione, or tissue proteins, or nucleic acids (e.g., RNA, DNA) and undergo different metabolic reactions. 

Some of these oxidative metabolites are biologically active and may even be more toxic than their parent compounds. Conversion by conjugation reactions is considered to lead to termination of the toxicity of these compounds and excretion of the non-toxic conjugates.58 Oxidative metabolism of a parent compound can lead to different products which may be excreted at different rates, as has been demonstrated for hydroxylated benzo[a]pyrenes.58... 

Covalent protein adducts of quinones are formed through Michael-type addition reaction with protein sulfhydryl groups or glutathione. Metabolic activation of several toxins (e.g., naphthalene, pentachlorophenol, and benzene) into quinones has been shown to result in protein quinone adducts (Lin et al., 1997 Rappaport et al., 1996 Zheng et al., 1997). Conversion of substituted hydroquinones such as p-aminophenol-hydroquinone and 2-hromo-hydroquinone to their respective glutathione S-conjugates must occur to allow bioactivation into nephrotoxic metabolites (Dekant, 1993). Western blot analysis of proteins from the kidneys of rats treated with 2-bromo-hydroquinone has revealed three distinct protein adducts conjugated to quinone-thioethers (Kleiner et al., 1998). 

Figure 13.10. NAT-mediated metabolic activation of heterocyclic aromatic amines. 2-AF is not a NAT substrate for A-aectylation (compare with 2-NA, 4-ABP A-acetylation in Figure 13.9). 2-AF is detoxified by P4502B1 ring hydroxylation. 2-AF is also metabolized via P4501A2-mediated A-hydroxylation. The resultant A-hydroxy 2-AF is a good substrate of conjugation reactions by NATs as well as by UGTs and SULTs and is converted to reactive metabolites for DNA adduct formation.

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. 

Benzoyl peroxide, the active ingredient in some shampoos for dogs, is almost completely metabolized to benzoic acid in the epidermis. Benzoic acid undergoes conjugation with glycine, primarily in the liver, and is excreted in urine as hippuric acid. Methylation of norepinephrine to epinephrine, an A-transferase-mediated conjugation reaction, in human and animal skin preparations has been reported. ... 

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