Metabolic Interactions of Pesticides - Pesticide Biotransformation and Disposition - page 148

Table 7.1 In Vivo Assessment of Altered Microsomal Activities in Humans and Animals Using Test
Compounds
Test compound

Test Species Reference

Aminopyrene Breath test Human Jager et al. (1980)

Antipyrine Plasma half-life, urinary

excretion

Human, rat Mehta et al. (1982); Butler

and Dauterman (1989)

Caffeine Plasma half-life, urinary

excretion

Human Kadlubar et al. (1992); Relling

et al. (1992)

Chloramphenicol Plasma half-life Human Mehta et al. (1975)

Hexobarbital Sleep time Rat Butler and Dauterman (1988)

β-Methyldigoxin Plasma half-life, urinary

excretion

Human Hinderling and Garrett (1977)

Phenylbutazone Plasma half-life Human Krishnaswamy et al. (1981)

Procaine Paralysis Rat Butler and Dauterman (1988)

Salicylates Plasma half-life, urinary

excretion

Rat Yu and Varma (1982)

Theophylline Plasma half-life Human, rat Mehta et al. (1982); Butler

and Dauterman (1988)

Pesticides, and other xenobiotics, in addition to serving as substrates for a number
of xenobiotic-metabolizing enzymes (XMEs), may also serve as inhibitors or inducers
of these or other enzymes. Moreover, there are many compounds that first inhibit and
subsequently induce such enzymes as the microsomal monooxygenases. The situation
is even further complicated by the fact that, although some substances have an inher-
ent toxicity and are detoxified in the body, others without inherent toxicity can be
metabolically activated to become potent toxicants. The following is illustrative of the
situations that might occur involving two compounds: compound A, without inher-
ent toxicity, is metabolized to a potent toxicant. In the presence of an inhibitor of
its metabolism, there would be a reduction in toxic effect, while after exposure to an
inducer of the activating enzymes, there would be an increase. Conversely, the toxicity
of compound B, a toxicant that is metabolically detoxified, would be increased in the
presence of an inhibitor and decreased in the presence of an inducer.
In addition to these possible cases, the toxicity of the inhibitor or inducer, as well as
the time dependence of the effect, must also be considered, because, as mentioned previ-
ously, many xenobiotics that are initially enzyme inhibitors ultimately become inducers.
Interactions between components in mixtures that are more complex than binary mix-
tures represent a particularly intractable program that has not yet been well resolved.
Other xenobiotics, such as clinical or other drugs, or occupational chemicals,
by causing enzyme induction or inhibition, can affect the metabolism and thus the
toxicity of pesticides. Conversely, pesticides, by acting as either enzyme inducers or
inhibitors, can affect the metabolism of other xenobiotics, such as drugs, as well as the