Page 235 - The Toxicology of Fishes

Biotransformation in Fishes 215

S
CH O
CH 3 2
P O NO 2
CH CH O
3
2
Parathion

S
P O O
CH O
CH 3 2
Desulfuration Dearylation P OH
CH CH O
2
3
O
CH CH O Diethyl phosphate
2
3
P O NO 2 HO NO 2 OR
CH O
CH 3 2 S
2
CH 3 CH O
P OH
Paraoxon p–Nitrophenol
CH CH O
2
3
Diethyl
phosphorothionate
FIGURE 4.26 Metabolic pathway of parathion in channel catfish. (From Straus, D.L. et al., Aquat. Toxicol., 50, 141, 2000.
With permission.)
is exclusively responsible for this reaction (Perkins et al., 1999); however, no single CYP isoform appears
to predominate in the sulfoxidation of aldicarb. Rather, it is likely that several isoforms participate in
the reaction (Perkins et al., 1999). The reduced S-oxygenation of aldicarb in channel catfish relative to
rainbow trout may explain its resistance against aldicarb toxicity compared to rainbow trout, which
readily convert aldicarb to aldicarb sulfoxide (Perkins and Schlenk, 2000).
In summary, fish are capable of activating organophosphate esters to more potent cholinesterase
inhibitors. Species differences in the bioactivation and esterase-mediated cleavage of organophosphates
have been shown to greatly contribute to species differences in toxicity to these compounds. These data
argue for more studies to better characterize specific enzymes responsible for these transformations to
help identify sensitive populations of species that may be severely impacted by these compounds.

Conclusions
Biotransformation can be a very important process in the disposition and mechanistic determinations of
the mode of action of xenobiotics. Alterations in enzyme expression can dramatically affect the sensitivity
of an organism to the toxic insult of a xenobiotic or the disposition of endogenous substrates. Alteration
may occur as a result of genetics, diet, gender, environmental influences, or other xenobiotics. Under-
standing the latter is critical in risk evaluations of chemical mixtures. Very little is known regarding the
substrate specificities or the regulation of biotransformation enzymes in fish. Through advances in
genomic technologies and the use of fish models in human health research (e.g., zebrafish, medaka),
numerous genotypic discoveries have recently occurred. It is likely that phenotypic functionality studies
with heterologously expressed enzymes resulting from genomic examinations will help in better under-
standing biotransformation pathways in fish. In addition, more studies are needed with whole-animal
systems to better characterize in vivo pathways of chemical biotransformation in species other than
classic fish models. Such studies are imperative for physiologically based toxicokinetic (PBTK) models,
which may help better estimate dose and aid regulators in reducing uncertainty between species, thus
leading to more accurate evaluations of chemical risk.