Sulfotransferase activities

In jji vitro N-hydroxy-MAB sulfotransferase-activating systems, N-sulfonyloxy-MAB also appears to undergo rapid reduction to MAB (Figure 9) with the concomitant oxidation of N-hydroxy-MAB to the N-arylnitrone (9) The oxidizing properties of the N-sulfonyloxy-MAB ion pair is consistent with results obtained for the primary... 

Beckmann JD, Bartzatt R, Ulphani J, et al. 1995. Phenol sulfotransferase activities and localization in human nasal polyp epithelium. Biochem Biophys Res Commun 213 104-111. 

The mouse has less sulfotransferase activity with respect to the a-hydroxytamoxifen, but more glucuronosyl transferase activity. The resulting glucuronic acid conjugation is a clear detoxication pathway, as a stable metabolite is formed, which can be readily eliminated. Hence, the mouse is much less susceptible, and although some tamoxifen is covalently bound to liver DNA, no hepatic tumors have been detected. 

The question however is what happens in humans Fortunately, it seems that humans have more glucuronosyl transferase activity than mice and much more than (100 x) rats (in which it is negligible). Furthermore, humans have much lower levels (5x) of sulfotransferase activity with this substrate, and so humans are the opposite extreme to rats. In studies in women treated with tamoxifen, no DNA adducts were detected in tissue samples, and liver tumors have not been detected. 

It has been proposed that 8-aminodcoxyguanosinc is formed from the nitronate tautomer of 2-nitropropane either by base nitrosation followed by reduction, or via an enzyme-mediated conversion of the nitronate anion to hydroxyiam ine-O-sulfonate or acetate, which yields the highly reactive nitrenium ion NHj (Sodum et al., 1993). Sodum et al. (1994) have provided evidence for the activation of 2-nitropropane to an aminating species by rat liver aryl sulfotransferase in vitro and in vivo. Pretreatment of rats with the aryl sulfotransferase inhibitors pentachlorophenol or 2,6-dichloro-4-nitrophenol significantly decreased the levels of nucleic acid modifications produced in the liver by 2-nitropropane treatment. Partially purified rat liver aryl sulfotransferase activated 2-nitropropane and its nitronate at neutral pH to a reactive species that aminated guanosine at the position. This activation was dependent on the presence of the enzyme, its specific cofactor adenosine 3 -phosphate 5 -phosphosulfate, and mercaptoethanol. It was inhibited... 

Sulfotransferase activity is not restricted to minoxidil. The ability of other pyrimidine-, as well as pyridine-, triazine- and imidazole N-oxides to serve as substrates was investigated using soluble liver preparation and PAPS. The variety of structures studied indicated that heteroaromatic N-oxides are generally metabolized by sulfotransferases183. Presumably, all of the heterocycles tested were conjugated via their N-oxide oxygens. 

Strychnine, which is detoxified by microsomal monooxygenase action, is more toxic to animals on low-protein diets, whereas octamethylpyrophosphoramide, carbon tetrachloride, and heptachlor, which are activated by monooxygenases, are less toxic. Phase II reactions may also be affected by dietary protein levels. Chloramphenicol glu-curonidation is reduced in protein-deficient guinea pigs, although no effect is seen on sulfotransferase activity in protein-deficient rats. 

C-sialyl moieties into liposomes showed excellent inhibition of viral binding.28 For practical applications, such moieties have also been integrated into molecular scaffolds for identifying GlcNAc 6-O-sulfotransferase activity specific to lymphoid tissue.29... 

Chen et al. (1999,2003) used cytosol prepared from various sections of the human intestine to study the occurrence and distribution of sulfotransferases in the gastrointestinal tract. They fortified the cytosol with PAPS. They utilized the sulfuryl group transfer from p-nitrophenol sulphate to PAP to generate PAPS for measurement of the phenol sulfotransferase activity by measurement of the colored product p-nitro-phenol. Cytosolic incubation were stopped by addition of Tris buffer, pH 8.7. 

Figure 9.18 shows a representative chromatogram of the substrates and products of liver monoamine oxidase activity. Figure 9.19 illustrates results with phenol sulfotransferase activity. 

Figure 9,19 Chromatograms of the cosubstrate (PAPS) and products of liver phenol sulfotransferase activity. Upper tracing a, PAPS, b, sulfate-conjugated dopamine. Middle tracing a, PAPS, b, sufate-conjugated Dopac. Lower tracing a, PAPS, b, sulfate-conjugated phenol. The retention time for sulfate-conjugated dopamine, Dopac, and phenol was 4.5, 6.8, and 7.0 minutes, respectively. (From Sim and Hsu, 1990.)...

Figure 9.143 Effect of incubation time on enzyme activity. Sulfotransferase activity was measured by the amount of j3-naphthol sulfate produced after varying incubation time periods. (From To and Wells, 1984.)...

Xenobiotic food additives, drugs, and biologically active endogenous compounds can interact and affect body biochemistry. For example, dopamine sulfotransferase activity is strongly inhibited by the colorant tartrazine and flavorant vanillin, and vanillin, erythrosine B, and octyl gallate inhibit the sulfation of 17 alpha-ethinylestradiol, a xenobiotic steroid J75l... 

Figure 4. Arylsulfatase activity ( - ) and sulfotransferase activity (a-a) in developing larvae of the southern armyworm (. eridania).

Glatt, H Davis, W., Meinl, W., Hermersdorfer, H., Venitt, S. and Phillips, D.H. (1998) Rat, but not human, sulfotransferase activates a tamoxifen metabolite to produce DNA adducts and gene mutations in bacteria and mammalian cells in culture. Carcinogenesis, 19, 1709-1713. 

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. 

S., Plaxco,)., Kadlubar, F.F., and Lang, N.P. (2000) Relationship of phenol sulfotransferase activity (SULT1A1) genotype to sulfotransferase phenotype in platelet cytosol. Pharmacogenetics, 10, 789-797. 

Enzyme activity is present in Ever, and exhibits some steroid specificity [128]. The measured for cholesterol is 0.02 mM [128]. Appreciable amounts of steroid sulfotransferase activity have also been found in adult mammalian adrenals, testes, and ovaries [129]. 

Four isoforms of NDST have been identified in human and mouse." " The isoforms can be divided into two subgroups NDST-1 and NDST-2 with 70% identities in amino acid sequence, andNDST-3 and NDST-4 with 80.4% identity. Those four NDST isoforms have distinct tissue expression patterns. NDST-1 and NDST-2 are expressed quite uniformly in different tissues, while the expression of NDST-3 and NDST-4 occurs predominantly in the brain. The NDST isoforms seem to have distinct deacetylase and sulfotransferase activities, with comparable levels of each. For example, NDST-3 has good deacetylase activity but very poor sulfotransferase activity, and NDST-4 shows the opposite with poor deacetylase activity and excellent sulfotransferase activity. The biological significance of the variations of the enzymatic activities of NDST isoforms is not fully understood, but it has been proposed that it may help generate unique sulfation patterns on HS." ... 

Hasegawa N, Torii T, Kato T, Miyajima H, Furuhata A, Nakayasu K, Kanai A, Habuchi O. Decreased GlcNAc 6-O-sulfotransferase activity in the cornea with macular corneal dystrophy. Invest Ophthalmol Vis Sci 2000 41 3670-3677. 

The manufacturer of etoricoxib recommends care when using etoricoxib with drugs that are metaboiised by human sulfotrans-ferases (they name oral salbutamol and minoxidil). This is because etoricoxib is an inhibitor of human sulfotransferase activity, and may increase the levels of these drugs. The increase in ethinylestradiol levels with etoricoxib is thought to be via this mechanism, see Hormonal contraceptives or HRT + Coxibs , p.994. 

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