Biotransformation (Metabolism) of Pesticides - Pesticide Biotransformation and Disposition - page 79

high level of oxidative metabolism in the liver makes this organ a possible target for
more toxic metabolic product activation when detoxifying and protective mechanisms
are overwhelmed. Both acute pesticide poisoning with liver involvement and chronic
liver toxicity, including cancer, have been associated with pesticide exposure.
CYP and FMO Monooxygenation
As illustrated in Table 5.1 , CYP carries out many different types of monooxygenation
of pesticide substrates, such as epoxidation (e.g., aldrin), N - dealkylation (e.g., atra-
zine), O - dealkylation (e.g., chlorfenvinphos), sulfoxidation (e.g., phorate), and oxida-
tive desulfuration (e.g., parathion) ( Ecobichon, 2001; Kulkarni and Hodgson, 1980,
1984a,b; Hodgson and Meyer, 2010 ). Substrates for FMO are similarly diverse, but all
are soft nucleophiles, a category that includes many organic chemicals containing sul-
fur, nitrogen, phosphorus, or selenium heteroatoms. Although CYP isoforms appear to
prefer hard nucleophiles as substrates, there is considerable overlap, and most, if not all,
substrates for FMO are also CYP substrates. The reverse, however, is not true, since
oxidation at carbon atoms is readily catalyzed by CYP but rarely, if at all, by FMO.
Moreover, even when the same substrate is oxidized by both CYP and FMO, there
may be differences in the rate of oxidation, in the products, or in the stereochemis-
try of the same product. While isoforms of both CYP and FMO are expressed in the
liver, they are broadly expressed in other organs, the proportions of different isoforms
varying from organ to organ. Pesticide substrates for FMO include organophosphates
such as phorate, disulfoton, and demeton-O, which yield sulfoxides; the phosphonate
fonofos, which yields fonofos oxon; carbamates such as aldicarb, methiocarb, and ethio-
fencarb; dithiocarbamate herbicides such as sodium metham; botanical insecticides such
as nicotine; and cotton defoliants such as the trivalent organophosphorus defoliant
folex ( Buronfosse et al., 1995; Furnes and Schlenk, 2005; Krueger and Williams, 2005;
Smyser and Hodgson, 1985 , 1986; Smyser et al., 1985; Tynes and Hodgson, 1985a,b;
Venkatesh et al., 1992a ).
Over 7500 animal CYP isoforms in 781 gene families have been characterized across
all taxa, and genomic and protein sequences are known. A system of nomenclature based
upon derived amino acid sequences was proposed in 1987, and entries are continuously
updated ( http://drnelson.utmem.edu/CytochromeP450.html ). The degree of similar-
ity in sequence classifies members into a CYP numeric gene family and then a letter
subfamily ( Nelson, 2006 ), such that individual isoforms have unique CYP number-
letter-number annotations, e.g., CYP1A1. Of the 110 animal CYP families, 18 are
found in vertebrates (Nelson, 2006). The total number of functional CYP genes in any
single mammalian species is thought to range from 60 to 200 ( Gonzalez, 1990 ). Whereas
some CYP isoforms are substrate specific, those involved in xenobiotic metabolism tend
to be relatively nonspecific, although substrate preferences are usually evident. FMOs,
like CYPs, are located in the endoplasmic reticulum of hepatocytes and other vertebrate