Sulfation of minoxidil by multiple human cytosolic sulfotransferases
Introduction
Minoxidil (6-(1-piperidinyl)-2,4-pyrimidinediamine-3-oxide), an antihypertensive agent and hair growth promoter, is unique because it is activated by sulfate conjugation to the active metabolite minoxidil sulfate 1, 2, 3, 4, 5, 6, 7, 8. It was initially thought that thermostable phenol sulfotransferase (TS PST or P-PST) catalyzed the reaction (9, 10, Fig. 1). This activity was designated minoxidil sulfotransferase (MNX-ST). The active minoxidil sulfate is required for the hypotensive effect and for the stimulation of hair growth 3, 5, 8. Sulfotransferase activity toward minoxidil is localized in the monkey and rat hair follicle and skin 11, 12, 13but little is known about such activity in human skin.
Human platelet, liver and gut levels of PST activities show wide individual variations 14, 15, 16, 17, 18, 19. The platelet levels of TS PST have been particularly interesting because they are significantly correlated with the corresponding TS PST levels in the human liver, cerebral cortex and small intestinal mucosa 17, 18, 19. Thus, it should be feasible to use a test of the easily obtained blood platelet enzyme activity to reflect the potential drug metabolizing activity in other tissues of interest. Knowledge about human sulfotransferase activities toward minoxidil would be useful in developing the capacity to predict individual responses to minoxidil. Therefore, we carried out the studies reviewed in this manuscript to begin to test the hypothesis that a measure of the level of human blood platelet minoxidil sulfotransferase activity would predict an individual’s physiologic response to minoxidil. Additional questions addressed in the work determined whether there were sulfotransferase activities in human skin, whether these activities were the same as known platelet and liver sulfotransferase activities and whether any skin sulfotransferase activities were correlated with the relative platelet sulfotransferase activities. To approach these questions, human cytosolic sulfotransferases from platelet homogenates and partially purified platelet enzymes, scalp skin high speed supernatants and COS-1 cell cDNA expressed preparations were studied using a radiochemical enzymatic assay with minoxidil as the substrate 20, 21, 22, 23.
The emerging sulfotransferase classification and nomenclature eventually will ease the burden of identifying the enzymes being discussed 24, 25, 26. There are at least five characterized human cytosolic sulfotransferases; hTSPST1 (thermostable phenol sulfotransferase, SULT 1A1), hTSPST2 (SULT 1A2), hTLPST (thermolabile phenol sulfotransferase, SULT 1A3), hEST (estrogen sulfotransferase, SULT 1E1) and hDHEAST (dehydroepiandrosterone sulfotransferase, SULT 2A1). hTSPST1 is the major TS PST studied based on known substrate specificities and the use of the term TS PST will indicate hTSPST1. TL PST will be used for hTLPST, EST for hEST and DHEA ST for hDHEAST throughout this presentation.
Section snippets
Human scalp skin phenol sulfotransferases
Interest in the presence of phenol sulfotransferases in scalp skin has arisen due to the widespread use of topical minoxidil preparations for the treatment of androgenic alopecia 3, 11, 27. Detection and careful biochemical characterization of human scalp skin phenol sulfotransferases would be a necessary step toward determining whether a measurement of platelet PST activity would reflect or predict the scalp skin activity, and thus, the potential response of an individual to topical minoxidil.
Partially purified human platelet sulfotransferases
A confusing picture of the putative MNX-ST activity emerged. Thermal stability properties and sensitivities to DCNP were similar to TL PST activity behavior and there were significant positive correlations of MNX-ST activities with TL PST activities. Human platelet PST partially purified through DEAE anion exchange chromatography was used [20]to provide physically separated samples of TL PST and TS PST for testing with minoxidil as the substrate. When partially purified human platelet TL PST
Recombinant human liver sulfotransferases
The availability of cDNA clones of human cytosolic sulfotransferases provided the opportunity to test specific cDNA expressed sulfotransferases that were not contaminated with other similar enzymes 29, 30, 31, 32. COS-1 cells (an SV40 transformed simian cell line) were used for all expression studies. The cells were transfected by the calcium phosphate method [33]with the human liver cDNAs cloned into the EcoRI site of plasmid p91023(B) [34]. The cells were maintained and processed to high
Discussion
Minoxidil is widely used as a topical hair growth promoter and as an oral antihypertensive agent. Minoxidil sulfate is the active compound that leads to the therapeutic effect in both of these situations. Investigations of the sulfotransferases that catalyze minoxidil sulfation eventually may enhance the understanding of the regulation of the response to minoxidil treatment in alopecia and hypertension. Studies have shown that the phenol sulfotransferases TS PST and TL PST are present in human
Acknowledgements
We thank Gar Johnson, Ph.D., who, while with the Upjohn Company, contributed to these studies, and Christopher Huerter, M.D., for doing the scalp skin biopsies; Richard Weinshilboum, M.D. and Diane Otterness for the generous gifts of the human liver TL PST, DHEA ST and EST cDNAs; Christine Halgard for her assistance with these studies; and the Upjohn Company for providing the minoxidil and minoxidil sulfate. This work was supported by the VA Medical Research Service (RJA, DLC), Nebraska
References (47)
- et al.
Sulfation of minoxidil by liver sulfotransferase
Biochem. Pharmacol.
(1982) - et al.
Minoxidil sulfate is the active metabolite that stimulates hair follicles
J. Invest. Dermatol.
(1990) - et al.
Enzymatic and non-enzymatic sulfation mechanisms in the biological actions of minoxidil
Biochem. Pharmacol.
(1993) - et al.
Sulfation of minoxidil by human liver phenol sulfotransferase
Biochem. Pharmacol.
(1990) - et al.
Localization of minoxidil sulfotransferase in rat liver and the outer rooth sheath of anagen pelage and vibrissa follicles
J. Invest. Dermatol.
(1991) - et al.
Sulphate conjugation of minoxidil in rat skin
Biochem. Pharmacol.
(1993) - et al.
Human platelet phenol sulphotransferase: assay procedure, substrate and tissue correlations
Clin. Chim. Acta
(1981) - et al.
Human platelet thermostable phenol sulfotransferase: assay of frozen samples and correlation between frozen and fresh activities
Clin. Chim. Acta
(1990) - et al.
Characterization of recombinant human liver thermolabile phenol sulfotransferase with minoxidil as the substrate
Biochem. Biophys. Res. Commun.
(1995) - et al.
Characterization of recombinant human liver dehydroepiandrosterone sulfotransferase with minoxidil as the substrate
Biochem. Pharmacol.
(1997)
Structural similarity and diversity of sulfotransferases
Chem.-Biol. Interact.
Quantitative estimation of hair growth. I. Androgenetic alopecia in women: effect of minoxidil
J. Invest. Dermatol.
Human liver thermolabile phenol sulfotransferase: cDNA cloning, expression and characterization
Biochem. Biophys. Res. Commun.
Human liver estrogen sulfotransferase: identification by cDNA cloning and expression
Biochem. Biophys. Res. Commun.
A new technique for the assay of infectivity of human adenovirus 5 DNA
Virology
A rapid and sensitive method for quantitation of microgram quantities of protein utilizing the principle of protein-dye binding
Anal. Biochem.
Steroid sulfation by expressed human cytosolic sulfotransferases
J. Steroid Biochem. Mol. Biol.
Minoxidil sulfate, a metabolite of minoxidil
Drug Metab. Dispos.
Drug therapy: minoxidil and the treatment of severe hypertension
N. Engl. J. Med.
Pyrimidine and triazine 3-oxide sulfates: a new family of vasodilators
J. Med. Chem.
Minoxidil-induced hypertrichosis: treatment with calcium thioglycolate depilatory
South Med. J.
The use of minoxidil in the treatment of severe essential hypertension: a report on 100 patients
Clin. Sci. Mol. Med.
Purification and characterization of rat liver minoxidil sulphotransferase
Biochem. J.
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