Page 220 - The Toxicology of Fishes

200 The Toxicology of Fishes

Xenobiotic substrates Endogenous substrates
OH
O 2N OH
H
4–nitrophenol
HO H H
4–nonylphenol HO
estradiol
OH HO HO
O
HO HO
3–hydroxybenzo(a)pryrene NH 2
O
HO dopamine I
Cl Cl
n-propyl gallate H 2N I OH
HO Cl
HO O O I
Cl OH I
4–hydroxy–3,3ʼ,4ʼ,5–tetrachlorobiphenyl OH thyroxine
HO O O
H
OH OH
N H H
O OH O
H 3C quercetin HO
3-β-hydroxyandrost–5–en–17–one
N–hydroxy-2-acetamidofluorene
(DHEA)
FIGURE 4.17 Selected xenobiotic and endogenous substrates for PAPS–sulfotransferase.

in bile and urine. Sulfate conjugates are also susceptible to hydrolysis by sulfatase, yielding back the
parent substrate; for example, sulfate conjugates formed in liver may be excreted in part into the bile.
The bile will be secreted into the intestine following a meal, where it may be hydrolyzed back to the
starting compound by intestinal sulfatases. The parent compound may be reabsorbed and reconjugated
in the liver (where it may undergo another round of biliary cycling) or may be conjugated by glucu-
ronidation or sulfonation in the intestine and excreted.
Pollutant compounds that are potential substrates for SULTs include phenol and phenol derivatives,
phase I hydroxylated metabolites of polycyclic aromatic hydrocarbons and polychlorinated biphenyls,
aryl amines and their hydroxylated metabolites, and other xenobiotics and their metabolites with hydroxyl
or amino groups in the molecular structure. Several physiologically important substrates such as steroids,
bile acids, and neurotransmitters are also substrates for sulfation. Examples of xenobiotic and physio-
logically important substrates are shown in Figure 4.17.
In some cases, sulfonation is a detoxication pathway, but in other cases formation of the sulfate ester
or the sulfamate leads to activation of the chemical to a reactive metabolite; for example, sulfonation of
hydroxylated (phenolic) metabolites of PAHs is a detoxication pathway (Figure 4.18A). The conjugate
is more water soluble and more readily excreted than the parent compound. Similarly, sulfonate conju-
gates of ring hydroxylated metabolites of N-acetylaminofluorene are relatively stable, water-soluble
metabolites that are readily excreted. On the other hand, sulfonation of benzylic hydroxy groups, formed
from hydroxylation of the methyl group in methylated PAHs (e.g., 6-hydroxymethyl-benzo(a)pyrene,
7-hydroxymethyl-12-methyl-benz(a,h)anthracene), may be an activation pathway (Watabe, 1983) (Figure
4.18B). This is because a sulfate group attached to an aliphatic carbon, especially a benzylic carbon, is
a good leaving group and yields the carbocation that can alkylate DNA. In another example, sulfonation
of N-hydroxyacetylaminofluorene gives an unstable product that decomposes to sulfate and the nitrenium
ion, which can alkylate DNA (DeBaun et al., 1968) (Figure 4.19).
In addition to its importance in toxication and detoxication, sulfonation is an important pathway for
transport and storage of several endogenous compounds. Estradiol, dehydroepiandrosterone (DHEA),
and other hydroxylated steroids are readily sulfonated; they may be transported around the body as the
sulfate conjugates and then hydrolyzed back to the active steroid at the target organ (Coughtrie et al.,