Sxp

Figure 18.4 Reduction biotransformation reactions.

performed oxidatively by replacing a hydrogen and a halogen with oxygen, or by eliminating two adjacent halogens and forming a carbon-carbon double bond.)

Hydrolysis Esters, epoxides, and amides are subject to hydrolysis catalyzed by a variety of enzymes (Figure 18.5). One important group is the cholinesterases, which include acetylcholinesterase. This was described above, although in the context of the toxic effect of pesticides. Carboxylesterases bind or hydrolyze organophosphorus pesticides. Epoxide hydrolase converts epoxides, such as those formed by cytochrome P450 enzymes, into diols. This protects against the genotoxic effect of the epoxides.

18.5.2 Phase II Reactions

Conjugations These phase II reactions involve combining the toxin with another molecule or functional group. These usually increase polarity, and therefore solubility, to facilitate excretion. Phase II reactions usually take place in the cytoplasm rather than in microsomes. They tend to be faster than phase I reactions, making the latter a rate-limiting step.

The most important detoxification mechanism is the conjugation with glucuronic acid (Figure 18.6). The enzyme responsible for it is found in the endoplasmic reticulum of many tissues, but especially in the liver. Many classes of compounds can be glucuroni-dated, including aliphatic and aromatic alcohols and amines.

Other conjugations involve addition of amino acids such as glutamine or glycine, or sulfate, methyl, or acetyl groups. The enzymes for these processes are found in the endoplasmic reticulum and the mitochondria, but mostly in the cytoplasm of hepatic cells. Methylation differs from the other phase II conjugations in that it tends to reduce aqueous solubility rather than increase it. The methyl group is usually added to a heteroatom (O, N, or S). A rare exception is the methylation of a carbon in benzo[a]pyrene to form 6-methylbenzo[a]pyrene.

a) Aliphatic ester

II esterase |l

ester acid alcohol b) Organophosphate ester

organophosphate ester acid alcohol c) Peptide bond

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