Biotransformation (Metabolism) of Pesticides - Pesticide Biotransformation and Disposition - page 93

pesticides are summarized in Table 5.3 . A database—In Vitro Human Metabolism of
Agrochemicals and Related Chemicals ( Hodgson, 2011 )—is available through the
Foundation for Toxicology and Agromedicine ( www.toxicologyagromed.org ) .
TOXICITY OF METABOLITES
In general, metabolites are less toxic than their parent compounds, if for no other rea-
son than that they are usually more water soluble and, therefore, more rapidly excreted.
There are notable exceptions in which biotransformation results in an inherently more
toxic product. Such reactions are generally referred to as activation reactions. These
reactive metabolites may combine covalently with cellular constituents such as DNA,
RNA, or proteins, and carcinogenesis, mutagenesis, and cellular necrosis are often
attributable to such reactive metabolites ( Anders et al., 1992; Guengerich, 1992, 1993;
Levi and Hodgson, 2001; Parke, 1987 ). Hollingworth et al. (1995) reviewed reactive
metabolites with particular reference to agrochemicals,
The metabolic production of a more toxic compound is sometimes called lethal
synthesis to emphasize that biotransformation in this instance is the source of danger.
The term lethal synthesis was introduced in a lecture given on June 7, 1951, by Peters
(1952) in connection with fluoroacetic acid. This compound is not itself an enzyme
inhibitor, but is converted by enzymes into a highly toxic material. Peters (1963) later
reviewed and extended the concept of lethal synthesis, although the term itself is now
seldom used.
The effects of metabolism may be complex, as illustrated by studies of bromoben-
zene. It has been known for some time that the liver necrosis associated with this com-
pound is caused by one or more toxic metabolites. Stimulation of its biotransformation
by phenobarbital potentiates the injury of toxic doses to the liver, and inhibition of
its metabolism by SKF 525-A prevents this injury. However, although 3-methylcho-
lanthrene causes a slight in vitro stimulation of the metabolism of bromobenzene and
does not alter the overall rate in vivo, it does protect against the hepatotoxicity. Rats
dosed with bromobenzene after induction with 3-methylcholanthrene excrete more
bromophenyldihydrodiol, bromocatechol, and 2-bromophenol than do uninduced rats.
The increase in the first two compounds suggests an increased capacity to detoxify
the highly reactive epoxide. The increase in 2-bromophenol suggests that induction
by 3-methylcholanthrene diverts the metabolism of bromobenzene to a comparatively
nontoxic pathway ( Zampaglione et al., 1973 ).
The role of metabolic activation in the carcinogenic process, particularly in the for-
mation of DNA adducts by reactive metabolites, has been of particular concern. For
example, monooxygenase enzymes have been postulated to play a role in the meta-
bolic activation of alachlor and metolachlor ( Brown et al., 1988; Feng and Wratten,
1989; Feng et al., 1990; Jacobsen et al., 1991; Li et al., 1992 ). Although studies suggest