45% amino acid sequence identity, while subfamily members share at least
60% homology. Each family is designated by an Arabic numeral following the
‘‘SULT’’ abbreviation, followed by an alphabetical subfamily, and the unique
isoform identified by an Arabic numeral. Thus, SULT4A1 belongs to family 4
subfamily A. To date, 11 SULT isoforms have been discovered in humans, and
these are listed in Table 3.5. Each isoform catalyzes the sulfonation of specific
substrates, although overlapping substrate specificity has been noted. The
SULT1A1 isoform catalyzes sulfonation of several small planar phenols, while
SULT1A3 is responsible for the conjugation of catecholamines. The main
substrates of the SULT1B subfamily are thyroid hormones. Human SULT1C
catalyzes the conjugation of some procarcinogens, while SULT1E1 is the main
isoform responsible for estrogen sulfation. Although SULT4A1 expression has
been reported in the brain, its function is as yet undetermined. Recent research
indicated a possible association of the SULT4A1 gene with schizophrenia
susceptibility (Brennan and Condra, 2005).
The crystal structures of some rodent and human SULTs have been
characterized (Gamage et al., 2005). Generally, SULT proteins have a highly
conserved PAPSbinding region and a variable hydrophobic substra-
tebinding site. The substratebinding pocket is variable and can therefore
accommodate different types of substrates; this flexibility is in the substra-
tebinding region also explains overlapping substratespecificity among
SULT family members.
3.2.3 Inducibility
Very little is understood about SULT gene regulation and tissue-specific
expression. The cloned humanSULT1AgeneswereshowntolackTATAor
CCAAT boxes near their putative transcriptional start sites (Aksoy and
Weinshilboum, 1995; Her et al., 1996; Raftogianis et al., 1996). Studies have
indicated that there is a marked difference in SULT gene regulation among
species. Thus, several glucocorticoids and glucocorticoid-like chemicals
induce bovine and rat SULT1A1 mRNA levels as well as protein levels, but
no such effect is observed in human cells (Beckmann et al., 1994; Duanmu
et al., 2000; Liu and Klaassen, 1996; Runge-Morris et al., 1996). Inducibility in
the rat is probably via glucocorticoid receptor or PXR (Duanmu et al., 2002;
Runge-Morris et al., 1999; Sonoda et al., 2002). Recent studies with the novel
human CAR activator Citco have yielded contradictory results in human
hepatocytes, with SULT1A1 mRNA induction reported in one sample, but no
induction in an independent study (Maglich et al., 2003; Pacifici and
Coughtrie, 2005).
3.2.4 SULT Pharmacogenetics
Much research has been conducted on characterization of genetic polymorph-
isms inSULTgenes (Coughtrie, 2002; Blanchard et al., 2004; Raftogoanis et al.,
CYTOSOLIC SULFOTRANSFERASES 65