Minoxidil Sulfotransferase, a Marker of Human Keratinocyte Differentiation

Johnson, George; Baker, Carolyn A.; Knight, Karen A.

doi:10.1111/1523-1747.ep12499930

Cited by 18 publications

(11 citation statements)

References 16 publications

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“…The synthesis of cholesterol sulfate in the epidermis is catalyzed by the enzyme cholesterol sulfotransferase. Cholesterol sulfotransferase activity increases with keratinocyte differentiation, and recent studies have shown that SULT2B1b is the isoform that accounts for the cholesterol sulfotransferase activity in the epidermis (14)(15)(16). For information on the organization of lipids in the stratum corneum, a recent review by Bouwstra and Ponec (17) provides a comprehensive state-of-the-art update.…”

Section: Jlr: Dr Feingold What Is the Key Function Of The Skin?mentioning

confidence: 99%

Thematic review series: Skin Lipids. The role of epidermal lipids in cutaneous permeability barrier homeostasis

Feingold

2007

Journal of Lipid Research

360

366

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The permeability barrier is required for terrestrial life and is localized to the stratum corneum, where extracellular lipid membranes inhibit water movement. The lipids that constitute the extracellular matrix have a unique composition and are 50% ceramides, 25% cholesterol, and 15% free fatty acids. Essential fatty acid deficiency results in abnormalities in stratum corneum structure function. The lipids are delivered to the extracellular space by the secretion of lamellar bodies, which contain phospholipids, glucosylceramides, sphingomyelin, cholesterol, and enzymes. In the extracellular space, the lamellar body lipids are metabolized by enzymes to the lipids that form the lamellar membranes. The lipids contained in the lamellar bodies are derived from both epidermal lipid synthesis and extracutaneous sources. Inhibition of cholesterol, fatty acid, ceramide, or glucosylceramide synthesis adversely affects lamellar body formation, thereby impairing barrier homeostasis. Studies have further shown that the elongation and desaturation of fatty acids is also required for barrier homeostasis. The mechanisms that mediate the uptake of extracutaneous lipids by the epidermis are unknown, but keratinocytes express LDL and scavenger receptor class B type 1, fatty acid transport proteins, and CD36. Topical application of physiologic lipids can improve permeability barrier homeostasis and has been useful in the treatment of cutaneous disorders.-Feingold, K. R. The role of epidermal lipids in cutaneous permeability barrier homeostasis. J. Lipid Res.

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Section: Jlr: Dr Feingold What Is the Key Function Of The Skin?mentioning

confidence: 99%

Thematic review series: Skin Lipids. The role of epidermal lipids in cutaneous permeability barrier homeostasis

Feingold

2007

Journal of Lipid Research

360

366

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“…when premature loss of proliferative po tential is suspected, as in AGA) and concomi tantly retard premature commitment to dif ferentiation pathways. The main argument in favor of this view is that Minoxidil is likely to act on cells which have committed to differen tiate (a) because Minoxidil sulfotransferase activity (essential for Minoxidil sulfation to Minoxidil sulfate, suspected to be the active metabolite) is only present on differentiating keratinocytes [43], and (b) because active K+ channels (the pharmacological target of Mi noxidil sulfate) have only been detected on involucrin-positive keratinocytes [44].…”

Section: Minoxidil On Nhk Prolifcration/differentiationmentioning

confidence: 99%

Biphasic Effects of Minoxidil on the Proliferation and Differentiation of Normal Human Keratinocytes

Boyera

Galey

Bernard³

1997

Skin Pharmacol Physiol

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Minoxidil is the most used drug with proved effects in the treatment of androgenetic alopecia (AGA), but little is known about its pharmacological activity and target cells in hair follicles. As AGA is characterized by follicle atrophy, accelerated hair cycles and hair fiber thinning, we postulated that kerati-nocyte proliferation/differentiation is affected and we tested Minoxidil’s effects on those parameters. Normal human keratinocytes (NHK) of follicular or epidermal origin were cultured in the presence of Minoxidil (0, 0.1, 1, 10, 100, 1,000 μM) during 5-8 days in various media (high-/low-calcium content, with or without serum). Proliferation was assessed by mitochondrial dehydrogenase activity (XTT), BrdU incorporation, lysosome numeration (neutral red incorporation) and total protein dosage. Drug-induced cytotoxicity was measured by lactate dehydrogenase release in culture supernatant, and pro-differentiating effects were evaluated by relative involucrin expression (ELISA dosage). On this basis, we showed that Minoxidil had biphasic effects on the proliferation and differentiation of NHK: Minoxidil stimulated NHK proliferation at micromolar doses, while antiproliferative, pro-differentiative and partially cyto-toxic effects were observed with millimolar concentrations. We can hypothesize that Minoxidil hypertrichotic activity in vivo is possibly mediated by the maintenance of proliferative potential in follicular keratinocytes precociously committed to differentiation.

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“…Another possibility is that, analogous to other N-oxides such as minoxidil (Hamamoto and Mori, 1989;Johnson et al, 1992;Baker et al, 1994), the N-oxide of lamotrigine could be a substrate for sulfotransferases leading to a N-sulfate, which might have sufficient chemical reactivity to bind to protein (Fig. 2).…”

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confidence: 99%

Possible Bioactivation Pathways of Lamotrigine

Lu¹,

Uetrecht²

2007

Drug Metab Dispos

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ABSTRACT:The anticonvulsant lamotrigine is associated with idiosyncratic drug reactions, especially skin rashes. Most idiosyncratic reactions are believed to be caused by reactive metabolites. Previous studies have found evidence that an arene oxide is formed in rats; however, when we incubated radiolabeled lamotrigine with rat liver microsomes virtually no covalent binding was detected, and the expected downstream phenolic metabolites are not observed in humans. Rare cases of agranulocytosis have been associated with lamotrigine therapy, and we found that lamotrigine is oxidized to two different N-chloro products by HOCl. The more reactive Nchloro metabolite forms an adduct with N-acetylhistidine, and covalent binding was observed when radiolabeled lamotrigine was incubated with myeloperoxidase/H 2 O 2 /Cl ؊ . Another lamotrigine metabolite is an N-oxide. If this N-oxide were sulfated, it might be sufficiently reactive to bind to protein. The synthetic N-sulfate reacted with N-acetylserine; however, no covalent binding was detected when the radiolabeled N-oxide was incubated with sulfotransferase. We also investigated the possibility that lamotrigine might be oxidized to a free radical by other peroxidases or oxidized by other enzymes such as prostaglandin H synthase or tyrosinase, but no evidence of oxidation was found, and lamotrigine did not cause any detectable increase in lipid peroxidation in vivo. In view of the virtual lack of covalent binding to hepatic microsomes and the lack of any other likely pathway leading to metabolic activation in the skin, it is possible that the parent drug rather than a reactive metabolite causes lamotrigine-induced skin rashes.

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Minoxidil Sulfotransferase, a Marker of Human Keratinocyte Differentiation

Cited by 18 publications

References 16 publications

Thematic review series: Skin Lipids. The role of epidermal lipids in cutaneous permeability barrier homeostasis

Thematic review series: Skin Lipids. The role of epidermal lipids in cutaneous permeability barrier homeostasis

Biphasic Effects of Minoxidil on the Proliferation and Differentiation of Normal Human Keratinocytes

Possible Bioactivation Pathways of Lamotrigine

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