Metabolic Interactions of Pesticides - Pesticide Biotransformation and Disposition - page 155

Dalton et al. (2003) , Das et al. (2006, 2008a,b) , and Johri et al. (2006, 2008) are among
the many examples cited throughout this chapter.
Abernathy et al. (1971a,b) demonstrated significant decreases in zoxazolamine paralysis
time, hexobarbital sleeping time, and aniline hydroxylase activity in mice following treat-
ment with dichlorodiphenyltrichloroethane (DDT) or 1,1-dichloro-2,2-bis( p -chloro-
phenyl)ethylene (DDE), a major metabolite of DDT and a persistent residue in animals,
including humans, even in countries where DDT use has been banned for decades.
Different inducers may increase the expression of different enzymes and, there-
fore, different metabolic pathways. Thus, Chadwick et al. (1971) showed that repeated
doses of lindane or DDT increased oxidative hydrolysis, O -demethylase, dehydro-
chlorinase, and glucuronyl transferase activity, but to different degrees. Pretreatment
of rats with lindane caused them to metabolize a single dose of radioactive lindane
2.5 times more extensively than controls, and pretreatment with DDT caused a 3.5-
fold increase in metabolism of radioactive lindane. Furthermore, the DDT pretreat-
ment was followed by generation of proportionally more neutral and weakly polar, but
less free-acid-type, metabolites of the radioactive lindane. Thus, metabolism was quali-
tatively as well as quantitatively different following administration of the two inducers.
Subsequent studies ( Chadwick and Freal, 1972 ) confirmed these findings, including
the increased excretion of metabolites following pretreatment with DDT. In addition,
it was shown that rats pretreated with DDT plus lindane excreted more 2,4,5-trichlo-
rophenol and 2,3,4,6- and 2,3,4,5-tetrachlorophenols by the second day of treatment
than did rats receiving lindane alone. The results suggested that DDT treatment stimu-
lates the metabolism of lindane through a selective effect on certain metabolic path-
ways involved in its oxidative degradation, notably those leading to the formation of
tetrachlorophenols, particularly 2,3,4,5-tetrachlorophenol.
Incidentally, when two inducers are involved, the resulting induction may be either
additive or slightly antagonistic. Thus, Gielen and Nebert (1971) found an additive
effect when either phenobarbital or p,p  -DDT was present with a polycyclic hydrocar-
bon, but not when combinations of phenobarbital plus DDT or one polycyclic hydro-
carbon plus another were involved.
Although it had been known for many years that various pesticides could induce
cytochrome P450s (CYPs), neither the specific isozymes induced nor the implications
of the induction were well characterized. Later studies using enzymatic and immuno-
chemical techniques examined isoform specificity of specific pesticides. For example,
mirex and chlordecone were shown to induce CYP2B10 and testosterone metabo-
lism in mouse liver, a pattern of induction similar to that of phenobarbital ( Baker
et al., 1972; Fabacher and Hodgson, 1976; Hodgson, 1974; Lewandowski et al., 1989 ).
Enzymatic activities suggested that, in addition to 2B10, other CYPs were induced,
and later studies demonstrated induction of CYP1A2 and CYP3A ( Dai et al., 1998;
Hodgson and Levi, 1996 ).