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Source: Williams and Burson (1985).

Source: Williams and Burson (1985).

TABLE 18.3 Substances That Inhibit Cytochrome P450

Piperonyl butoxide Aminotriazole Carbon tetrachloride

Chloramphenical a-Napthyl isocyanate Bromobenzene

Cobaltous chloride Carbon disulfide

Source: Williams and Burson (1985).

One important effect of cytochrome P450 monooxygenases is to convert aromatics into epoxides. It is thought that this metabolite is responsible for the cancer-causing behavior of aromatics such as benzene and benzo[a]pyrene. The epoxides are unstable and convert readily to phenols. Phenol is found in the urine of persons exposed to benzene. Other enzymes can convert epoxides into dihydrodiols, which are nontoxic and easily excreted.

Some chemicals, called inducers, increase the rate of biotransformation of other compounds by stimulating the synthesis of more cytochrome P450. Thus, these substances are likely to interact with other substances in a more than additive manner (Section 19.5). Table 18.2 lists some of these compounds.

Other compounds inhibit cytochrome P450 and thus may interact in a less than additive manner with other substances. Some of these are listed in Table 18.3. The effect of indu-cers and inhibitors can be used to show whether a substance or its metabolite is causing the toxic effect. For example, bromobenzene causes necrosis in the liver, which is increased by phenobarbital and decreased by other inhibitors. Therefore, the damage must be caused mostly by a metabolite.

The liver enzyme alcohol dehydrogenase converts ethanol into acetaldehyde, which is even more toxic than ethanol. This is followed by the action of aldehyde dehydrogenase, which forms easily excreted acids.

Reduction Under low-oxygen tension conditions, the cytochrome P450 monooxy-genase system is capable of catalyzing reduction of azo and nitro compounds to amines (Figure 18.4). Other types of compounds that are reacted reductively are those containing an aldehyde, ketone, disulfide, sulfoxide, quinone, N-oxide, or alkene group. Aldehydes are converted to alcohols and ketones to secondary alcohols.

Another reduction mechanism is the replacement of a halogen bonded to a carbon by a hydrogen (reductive dehalogenation). This is responsible for the hepatotoxicity of carbon tetrachloride and similar halogenated alkanes. (Dehalogenation can also be

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