Page 221 - The Toxicology of Fishes

Biotransformation in Fishes 201

A.
CYP SULT
OH
O
O S O
detoxication product OH

CH 3
B. CH 3
CYP
CH 2OH
CH 3
SULT

CH 3
CH 3
nonenzymatic
H 2C
O
CH 2
HSO 4 O S O
reactive carbocation OH
FIGURE 4.18 Sulfonation as a toxication or detoxication pathway. This figure shows examples of polycyclic aromatic
hydrocarbons that are metabolized to nontoxic (A) or reactive (B) sulfate esters. The example in (A) shows the oxygenation
of benzo(a)pyrene to 3-hydroxybenzo(a)pyrene, followed by sulfonation of the phenolic hydroxyl group to the nontoxic
sulfate ester. The example in (B) shows the oxygenation of one of the methyl groups in 7,12-dimethyl-benz(a,h)anthracene
to give 7-hydroxymethyl-12-methylbenz(a,h)anthracene, followed by sulfonation of the benzylic (alcohol-like) hydroxyl
group to the unstable sulfate ester. This ester can spontaneously eliminate the sulfate group, leaving the reactive carbocation
shown. The carbocation will react with cellular nucleophiles, possibly including DNA bases.

1998; Miki et al., 2002). The ability of the sulfonated steroid to cross cell membranes is sometimes
superior to that of the unconjugated steroid. This is in part because the conjugates are substrates for
several organic anion transporter proteins involved in the uptake as well as efflux of anions and in part
because of more favorable solubility characteristics for diffusion conferred by the addition of a polar
group to an otherwise poorly water-soluble molecule. The transport and hydrolysis of sulfonate conju-
gates of steroids have been described in mammals, but to date little direct evidence suggests this pathway
in fish. Not only are steroid hormones readily sulfonated but also other physiologically important
chemicals such as dopamine, related biogenic amines, and thyroid hormones. In the case of dopamine,
the amino group and the ring hydroxyl groups are potential sites of sulfonation. In the shark, the sterol
scymnol has been found as the sulfate ester, which appears to serve as a bile acid (Macrides et al., 1997).
Rainbow trout liver contains SULT activity that is active with thyroid hormones, especially 3,3′,5-
triiodothyronine (T ) (Finnson and Eales, 1998).
3
Evidence for the sulfonation pathway in fish has been sought by examining bile, urine, and tank water
of exposed fish for sulfonate conjugates, as well as by studying enzyme activity in vitro with the substrate
of interest (Finnson and Eales, 1996; James, 1986; James et al., 1997, 1998). Studies that demonstrate
sulfonation have also been conducted in hepatocytes and with in situ isolated preparations (Coldham et
al., 1998; Cravedi et al., 1999).

Gene Structure of SULT
Several SULT enzymes with differing substrate selectivities are known to exist in the liver and other
organs of humans (Coughtrie, 2002; Dooley, 1998). The nomenclature of the SULT enzymes was
originally based on the enzymatic function of the isolated isoforms; however, because recombinant DNA
techniques have become mainstream and additional SULT isoforms are being identified by their gene
structure, the need for a widely accepted nomenclature was recognized. This has led to a proposed