Sulfotransferases, role

The role of N-sulfonyloxy arylamines as ultimate carcinogens appears to be limited. For N-hydroxy-2-naphthylamine, conversion by rat hepatic sulfotransferase to a N-sulfonyloxy metabolite results primarily in decomposition to 2-amino-l-naphthol and 1-sulfonyloxy-2-naphthylamine which are also major urinary metabolites and reaction with added nucleophiles is very low, which suggests an overall detoxification process (9,17). However, for 4-aminoazobenzene and N-hydroxy-AAF, which are potent hepatocarcinogens in the newborn mouse, evidence has been presented that strongly implicates their N-sulfonyloxy arylamine esters as ultimate hepatocarcinogens in this species (10,104). This includes the inhibition of arylamine-DNA adduct formation and tumorigenesis by the sulfotransferase inhibitor pentachlorophenol, the reduced tumor incidence in brachymorphic mice that are deficient in PAPS biosynthesis (10,115), and the relatively low O-acetyltransferase activity of mouse liver for N-hydroxy-4-aminoazobenzene and N-OH-AF (7,114,115). 

O Leary, K.A., Day, A.J., Needs, P.W., Mellon, F.A., O Brien, N.M., and Williamson, G., Metabolism of quercetin-7- and quercetin-3-glucuronides by an in vitro hepatic model the role of human (3-glucuronidase, sulfotransferase, catechol-0-methyltransferase and multi-resistant protein 2 (MRP2) in flavonoid metabolism, Biochem. Pharmacol, 65, 479, 2003. 

Miksits M, Maier-Salamon A, Aust S, Thalhammer T, Reznicek G, Kunert O, Haslinger E, Szekeres T, Jaeger W. 2005. Sulfation of resveratrol in human liver Evidence of a major role for the sulfotransferases SULT1A1 and SULT1E1. Xenobiotica 35 1101-1119. 

Curcumin has also been found to interrupt the cell cycle, to have cytotoxic effects, and to have a role in antiproliferation and the induction of apoptosis in a hepatocarcinoma cell line. Curcumin is a potent inhibitor of phenol sulfotransferase (SULT1A1) in human liver and extrahepatic tissues [Vietri et al., 2003]. Curcumin inhibited the interleukin-6 (IL-6) production, histone acetyltransferase (HAT) activity, and API activation [Chen et al., 2003a] and prevented cell death and apoptotic biochemical changes, such as the... 

Busby WF, Ackermann JM, Crespi CL (1999) Effect of methanol, ethanol, dimethyl sulfoxide, and acetonitrile on in vitro activities of cDNA-expressed human cytochromes P-450. Drug Metab Dispos 27 246-249 Clohs L, Wong J (2002) Validation of a capillary electrophoresis assay for assessing the metabolic stability of verapamil in human liver microsomes. J Cap Elec Microchip Tech 7 113 Coughtrie MWH, Fisher MB (2003) The role of sulfotransferase and UDP-glucuronosyltransferases. In Lee JS, Obach RS, Fisher MB (eds) Drug Metabolizing Enzymes. Marcel Dekker, New York pp 541-575... 

Since liver is the most important organ for metabolism investigations the procedures described here focus on liver cytosol exemplarily. Liver cytosol fraction contains soluble Phase I and Phase II enzymes which play an important role in drug metabolism (Brandon 2003). These are alcohol and aldehyde dehydrogenases, epoxide hydrolases, sulfotransferases, glutathione S transferase, N-acetyl transferases, and methyl transferases. Therefore, in cytosolic preparations these biotransformation steps can be studied. Cytosolic fractions are commercially available (BDGentest, Invitro Technologies, Xenotech and others) or easy to prepare, alternatively. 

Thomas NL, Coughthrie MWH (2003) Sulfation of apomor-phine by human sulfotransferases evidence of a major role for the polymorphic phenol sulfotransferase. SULT1A1. Xenobiotica 33 1139-1148... 

The sulfated monosaccharides have been gaining prominence recently as they seem to play a well documented role as the critical components of the oligosaccharide ligands for the selectins. The structural and biochemical progress in this area is very fast with both the contribution from chemical synthesis and enzymology of the specific sulfotransferases [238]. 

Gamage N, Barnett A, Hempel N, Duggleby RG, Windmill KF, Martin JL, McManus ME. Human sulfotransferases and their role in chemical metabolism. Toxicol Sci 2006 90 5-22. 

Age. The pharmacokinetic and pharmacodynamic effects of a drug can be influenced by age, and drug metabolism plays an important role in understanding the differences observed. Differences between the levels of metabolism enzymes for the fetal and neonatal (first 4 weeks postpartum) liver versus the adult liver have been observed in both animal and human studies (125). At birth, total CYP levels are approximately 30%of adult levels and glucuronidation activity is at 10-30% of adult levels. Interestingly, sulfotransferase activity in neonates seems to be comparable with that in adults. 

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