3.2.8 Summary
Sulfotransferases are important Phase II enzymes that catalyze the conjugation
of numerous endogenous chemicals as well as several xenobiotics. SULTs exhibit
tissue-specific expression, but their gene regulation is poorly understood. SULT
pharmacogenetics have been evaluated and may account for some interindivi-
dual variability to xenobiotic exposure. Several chemicals are known to inhibit
SULTs, and this leads to numerous drug–drug and food–drug interactions.
3.3 Glutathione-S-Transferases
3.3.1 General Overview
GSTs catalyze the attack of the endogenous nucleophile, glutathione, to
electrophilic molecules. Glutathione is a tripeptide of glycine–cysteine–gamma-
glutamic acid. Glutathione is the major protective nucleophile in the body. GSTs
also catalyze the SN2 displacement of halogen atoms on halogenated alkanes and
aromatic halogens. The enzyme activates the cysteine thiol into a more
nucleophilic thiolate anion that then attacks an electrophilic center held in close
proximity to the thiolate. Glutathione transferases are active in their dimeric
forms. They can form either homodimers or heterodimers with two catalytic
centers. Heterodimers typically have intermediate activity between the two
homodimers. There are several major classes of glutathione-S-transferase. In
general, glutathione serves to protect against a number of carcinogens, but in
some cases can actually bioactivate compounds, for example, 1,2-dibromoethane
and sevoflurane. Kidney toxicity of sevoflurane (via Compound A) occurs via the
GST-mercapturate-beta lyase pathway (Goldberg et al., 1999). A number of
anticancer agents (nitrogen mustards, busulfan) and inhalation anesthetics
(halothane, enflurane, sevoflurane) are metabolized by GST enzymes.
Glutathione conjugates are excreted via transporters into the bile or are
converted to their mercapturic acid derivatives (N-acetyl cysteine conjugates) and
excreted into the urine. The GSTs have broad substrate specificity. They also play
an important role in arachidonic acid metabolism resulting in the formation of
leukotrienes. Prostaglandin A2 (PGA2), PGJ2, and D12PGJ2 (containing alpha-
beta unsaturated ketones) are substrates for GSTs (Boogaard et al., 1989). The
attenuation of PGJ 2 signaling results in upregulation of Nrf2-dependent and
PPARg-dependent gene expression and down regulation of NF-kB-dependent
gene expression (Park et al., 2004). There are excellent recent reviews on GSTs in
Methods of Enzymology(V. 401, 2005) and by Hayes et al. 2005.
3.3.2 Classification of the GST Enzymes
There are six major classes of the human cytosolic GST enzymes, namely, alpha,
mu, omega, pi, theta, and the newly discovered zeta class (Mannervik et al.,
2005). The sigma class is involved in prostaglandin metabolism (isomerization of
PGH 2 to PGD 2 ) (Jowsey et al., 2001). Kappa class enzymes are expressed in
72 CONJUGATIVE METABOLISM OF DRUGS