Understanding the molecular regulation of the
sulfotransferases is important because these
enzymes are essential to a number of critical biological processes.
Sulfotransferase expression clearly plays a role in
xenobiotic detoxication,
carcinogen activation,
prodrug processing, cellular signaling pathways, and the regulation of intratissue active
androgen and
estrogen levels. Although cytosolic
sulfotransferases are present in the gut, adrenal, kidney, lung, skin, brain, and other extrahepatic tissues, the basis for the molecular regulation of this complicated gene family has been best characterized in the rat liver, where
sulfotransferase levels are relatively abundant. Advances in genomic cloning and in the molecular characterization of individual
sulfotransferase cDNAs have inspired new insights into the mechanisms involved in
sulfotransferase gene regulation. In particular, the hypothalamic-pituitary-gonadal-adrenocortical axis appears to play a significant role in the regulation of individual
sulfotransferase genes. The molecular signals that fluctuate with developmental age, gender, and the occurrence of systemic endocrinopathies also influence
sulfotransferase gene expression. For example, diabetes, which disrupts
glucose and
ketone homeostasis,
insulin sensitivity, gonadal and neuroendocrine
hormone balance,
protein kinase C isoform expression, and P450 metabolism, also disturbs hepatic
sulfotransferase gene expression. What role does
sulfotransferase expression play in target organ toxicity? Do
xenobiotic-mediated changes in
sulfotransferase expression compromise detoxication? Does deregulated
sulfotransferase expression during development lead to
birth defects by perturbing the delicate balance of active
hormone levels in fetal tissues? Do conditions of
glucocorticoid excess, such as stress or high-dose
glucocorticoid therapy induce
sulfotransferase expression and place toxicant and
carcinogen bioactivation systems in overdrive? This review will summarize our current understanding of the molecular and cellular regulation of the major rodent cytosolic
sulfotransferases. Only by thoroughly dissecting the regulation of this important multigene family in rodent liver, where
sulfotransferase expression is most abundant, can we begin to focus on more pressing questions concerning the role of the
sulfotransferases in the genesis of endocrinopathies and
cancer in humans.