Metabolic Interactions of Pesticides - Pesticide Biotransformation and Disposition - page 167

human isoform CYP3A4 is significantly increased by incubation of the enzyme with
pyridostigmine bromide ( Usmani et al., 2003 ), and Buratti and Testai (2007) have pre-
sented evidence for the autoactivation of CYP3A4 during dimethoate metabolism.
More recently, Cho et al. (2007) have shown that chlorpyrifos oxon significantly acti-
vates the production of 1-naphthol, 2-naphthol, trans -1,2-dihydronaphthalenediol,
and 1,4-naphthoquinine from naphthalene by human liver microsomes. Further, it
was shown that production of naphthalene metabolites by CYPs 2C8, 2C9, 2C19,
2D6, 3A4, 3A5, and 3A7 was activated by chlorpyrifos oxon, while the production of
naphthalene metabolites by CYPs 1A1, 1A2, 1B1, and 2B6 was inhibited by chlorpyri-
fos oxon.
Activation effects on CYP metabolism of the insect repellent DEET ( N,N -diethyl-
m -toluamide) were also noted (Cho et al., 2007). Chlorpyrifos oxon inhibited the
formation of N,N -diethyl- m -hydroxymethylbenzamide from DEET by human liver
microsomes while stimulating the formation from DEET of N -ethyl- m -toluamide.
This was reflected by the finding that CYP2B6, the principal isoform for N,N -diethyl-
m -hydroxymethylbenzamide production, was inhibited by chlorpyrifos oxon, while
CYP3A4, the principal isoform for N -ethyl- m -toluamide production, was activated.
HEPATOTOXICITY
Hepatotoxicity has frequently been observed as a consequence of xenobiotic exposure.
Although XMEs and metabolic interactions may not be directly involved in hepato-
toxicity, some consideration should be given to this phenomenon, since loss of liver
function may well give rise to consequences and interactions not seen in the intact
liver. There have been a number of studies of enzyme induction in isolated hepato-
cytes from both surrogate animals and humans (see Induction of Microsomal Enzyme
Activity), but studies involving the toxic effects of pesticides on the hepatocytes of sur-
rogate animals have been relatively rare. The availability of the liver-derived HepG2
cell line and the more recent availability of human hepatocytes have, however, made
new approaches to this phenomenon possible.
Typically, cell viability and cytotoxicity are measured by the use of the trypan blue
exclusion method and the release of adenylate kinase into the medium. Apoptosis, or
programmed cell death, is examined by measuring the induction of caspase-3/7 (see
Das et al., 2006 , for a description of these methods). In both HepG2 cells and human
hepatocytes the following pesticides caused cell death, release of adenylate kinase, and
induction of caspase: fipronil and fipronil sulfone ( Das et al., 2006 ), deltamethrin and
permethrin ( Das et al., 2008a ), DEET ( Das et al., 2008b ), and chlorpyrifos ( Das et al.,
2008b ). The most potent of these is fipronil, while the least potent is DEET. Since
fipronil sulfone is more active than fipronil, the CYP-dependent monooxygenation of
fipronil may be considered an activation reaction.