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160 REACTIVE METABOLITES

CH3

O

NH

O

CH3

NH

Sulfotransferase

HO

Acetaminophen

UDP

TransferaseGlucuronide

CH3

O

NH

O3SO

 

P450

glucuronide-O

 

 

 

 

 

 

CH3

CH3

 

 

O

 

 

Covalent binding to SH groups

 

N

O

 

 

Glutathione

Transferase

NH

Cell death O

HO S-glutathione

N-acetylbenzoquinoneimine

NAPQI

Figure 8.6 Metabolism of acetaminophen and formation of reactive metabolites.

O

 

O

 

 

 

 

b-Glucosidase

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CH3N

 

NCH2-b-glucoside

 

CH3N

 

NCH2OH

 

 

 

 

 

 

 

 

 

 

(gut microflora)

 

 

 

Cycasin

 

Methylazoxymethanol

[Methylazoxymethanol

 

 

 

 

 

 

 

 

 

glucoside]

 

 

 

 

 

 

Figure 8.7 Bioactivation of cycasin by intestinal microflora to the carcinogen methylazoxymethanol.

8.7FUTURE DEVELOPMENTS

The current procedures for assessing safety and carcinogenic potential of chemicals using whole animal studies are expensive as well as becoming less socially acceptable. Moreover the scientific validity of such tests for human risk assessment is also being questioned. Currently a battery of short-termmutagenicity tests are used extensively as early predictors of mutagenicity and possible carcinogenicity.

Most of these systems use test organisms—forexample,bacteria—thatlack suitable enzyme systems to bioactivate chemicals, and therefore an exogenous activating system is used. Usually the postmitochondrial fraction from rat liver, containing both phase I and phase II enzymes, is used as the activating system. The critical question is, To what

SUGGESTED READING

161

extent does this rat system represent the true in vivo situation, especially in humans? If not this system, then what is the better alternative? As some of the examples in this chapter illustrate, a chemical that is toxic or carcinogenic in one species or gender may be inactive in another, and this phenomenon is often related to the complement of enzymes, either activation or detoxication, expressed in the exposed organism.

Another factor to consider is the ability of many foreign compounds to selectively induce the CYP enzymes involved in their metabolism, especially if this induction results in the activation of the compound. With molecular techniques now available, considerable progress is being made in defining the enzyme and isozyme complements of human and laboratory species and understanding their mechanisms of control. Another area of active research is the use of in vitro expression systems to study the oxidation of foreign chemicals (e.g., bacteria containing genes for specific human CYP isozymes).

In summary, in studies of chemical toxicity, pathways and rates of metabolism as well as effects resulting from toxicokinetic factors and receptor affinities are critical in the choice of the animal species and experimental design. Therefore it is important that the animal species chosen as a model for humans in safety evaluations metabolize the test chemical by the same routes as humans and, furthermore, that quantitative differences are considered in the interpretation of animal toxicity data. Risk assessment methods involving the extrapolation of toxic or carcinogenic potential of a chemical from one species to another must consider the metabolic and toxicokinetic characteristics of both species.

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