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Biochemistry of cytosolic sulfotransferases involved in bioactivation
1Department of Pharmacology, University of Alabama at Birmingham 35294.
Abstract:
Numerous studies have indicated that two classes of cytosolic STs are involved in the bioactivation of procarcinogens and drugs to reactive electrophiles, especially in rodent tissues. These two classes of STs are the hydroxysteroid STs, which are involved in the conjugation of hydroxymethyl PAHs, and the phenol STs involved in the sulfation of alkenylbenzenes and N-hydroxyarylamines. Purification studies of rat liver STs have clearly indicated that specific isoforms of hydroxysteroid and phenol STs are capable of sulfating procarcinogens in vitro. Rat liver STa and BAST I are structurally similar hydroxysteroid STs, which have been shown to sulfate and bioactive HMBA. Molecular cloning studies of the rat hydroxysteroid STs indicate that these enzymes are probably part of a family of closely related genes. The single human hydroxysteroid ST that has been characterized is very similar to the rat enzymes, but its role in the bioactivation of hydroxymethyl PAHs has not been established. Phenol STs have been demonstrated to have an important role in the bioactivation of alkenylbenzenes and N-hydroxyarylamines. Purification of rat phenol STs has identified several different forms, but only some appear to be involved in bioactivation of procarcinogens. Four isoforms (HAST I and II, AST III and IV) are apparently responsible for the majority of N-hydroxyarylamine sulfation. The relationship between these enzymes has not been established but they may represent similar enzymes. Different isoforms of rat phenol ST are also involved in the bioactivation of procarcinogens and drugs. However, the role of these phenol STs, PST-1, Mx-ST, and paracetamol ST, in carcinogenesis requires further study. In human tissues, only two phenol STs, P-PST and M-PST, have been identified. The role of these enzymes or unidentified STs in the sulfation of N-hydroxyarylamine procarcinogens has not yet been established. Initial reports of the molecular cloning and expression of the rat and human phenol ST genes will provide a valuable mechanism for the characterization of roles of the individual enzymes in bioactivation.
Insights
Cytosolic sulfotransferases (STs) bioactivate procarcinogens. Hydroxysteroid STs conjugate hydroxymethyl PAHs, while phenol STs sulfate alkenylbenzenes and N-hydroxyarylamines, crucial for drug and carcinogen metabolism.
Area of Science:
- Biochemistry
- Pharmacology
- Toxicology
Background:
- Cytosolic sulfotransferases (STs) are critical enzymes in xenobiotic metabolism.
- Two main classes, hydroxysteroid STs and phenol STs, are implicated in bioactivating procarcinogens and drugs.
- Their role in forming reactive electrophiles, particularly in rodent models, is well-documented.
Purpose of the Study:
- To review the roles of hydroxysteroid and phenol STs in the bioactivation of procarcinogens and drugs.
- To highlight findings from purification and molecular cloning studies in rodent and human tissues.
- To identify specific isoforms involved in sulfation pathways of carcinogens and drugs.
Main Methods:
- Purification of rat liver STs to identify specific isoforms.
- Molecular cloning and characterization of rat and human ST genes.
- In vitro studies assessing the sulfation activity of ST isoforms on procarcinogens.
Main Results:
- Specific rat liver hydroxysteroid STs (STa, BAST I) sulfate hydroxymethyl benzylarene (HMBA).
- Multiple rat phenol ST isoforms (HAST I-IV) are key in N-hydroxyarylamine sulfation.
- Human STs show similarity to rat enzymes, but their specific roles in bioactivation require further investigation.
Conclusions:
- Hydroxysteroid and phenol STs play distinct but vital roles in procarcinogen bioactivation.
- Isoform-specific activities are crucial for understanding their contribution to carcinogenesis.
- Further research on human STs is needed to elucidate their role in drug metabolism and cancer risk.