Page 219 - The Toxicology of Fishes

Biotransformation in Fishes 199

TABLE 4.16
Induction of GSTs by Xenobiotics in Aquatic Organisms
Inducers Effect
PAHs 3-MC No effect on activity in minnows and killifish,
variable pattern (±1.5-fold in flounder and plaice)
BNF No effect on activity, induction of GSTmRNA in
plaice, no effect on activity in trout.
Petroleum/oil Induced activity in scallop, mussel, and clam
PCBs Tetrachlorobiphenyl Induced activity in trout
Arochlor ® Induced GSTA in flounder and plaice, activity in
clams
Clophen Slight induction of activity in trout
Reactive epoxide trans-Stilbene oxide Induced GSTA in plaice and flounder
Antioxidants BHA Induced activity in plaice
Ethoxyquin Induced activity in salmon and possibly catfish
Pesticides 2,4-D Induced activity in carp and tilapia
Azinphosmethyl Induced activity in carp and tilapia
Carbaryl Induced activity in prawns
Endosulfan, p,p′-DDE, methoxychlor Induced activity in clams
Cypermethrin Induced activity in crabs
Peroxisomal proliferators Clofibrate, perflouroctanoic acid Induced plaice GSTA and GSTA1
(PPRE-γ agonists) (PFOA)
Cyanobacterial toxins Microcystins Induced activity in crabs

Inhibition of GSTs
Very little literature exists regarding the inhibition of GST activity; however, compounds that bind
covalently (e.g., carcinogens) or noncovalently (e.g., heme degradation products, hematin itself, and
bilirubin) will inhibit the activity of isoforms to which they are bound. Some xenobiotics may also be
inhibitors of GST. Although the binding constants for bilirubin and hematin for plaice liver cytosolic
GSTs are lower than those for mammalian GSTA1, these endobiotics do bind and act as inhibitors with
I values of 320 and 10 mM, respectively (George and Buchanan, 1990). Binding constants of these
50
compounds with purified GSTs from elasmobranchs were an order of magnitude lower than with plaice.
Of particular note is the very high potency of organotin compounds (tributyltin, triphenyltin) for inhibition
of plaice cytosolic GST activity in vitro (George and Buchanan, 1990).

Sulfotransferase

Overview
The sulfotransferase (SULT) family of enzymes catalyzes the transfer of the sulfonate group from
3′-phosphoadenosine-5′-phosphosulfate (PAPS) to hydroxyl (phenolic or alcoholic) and amine groups
in a range of endogenous and exogenous substrates (Coughtrie, 2002; Mulder, 1981):
ROH + PAPS → ROSO H + PAP
3
The cofactor for the sulfation reaction is 3′-phosphoadenosine-5′-phophosulfate and is synthesized from
adenosine triphosphate (ATP) and inorganic sulfate. The reaction uses two molecules of ATP per molecule
PAPS formed, which indicates the high-energy content of the cofactor (Falany, 1997). The rate of
formation of PAPS is relatively slow, and cellular levels of PAPS are usually low. This results in the
relatively low effectiveness of sulfation as a biotransformation pathway when organisms are exposed to
sudden increase of potential substrates. In addition, the desulfated reaction product of PAPS is still able
to bind to the active site of the enzyme and is therefore a potent inhibitor of the catalytic reaction.
Sulfate or sulfamate conjugates, once formed, are acidic molecules with pK values in the range of 2
a
to 4, and they exist largely as anions at physiological pH. Like other anions, they are readily excreted