Sulfation of minoxidil by multiple human cytosolic sulfotransferases

Anderson, Robert J.; Kudlacek, Patrick E.; Clemens, Dahn L.

doi:10.1016/s0009-2797(97)00120-8

Cited by 64 publications

(38 citation statements)

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“…Test compounds were selected based on either good activity toward the target enzymes-for example, 4-methylumbelliferone for UGTs (Manevski et al, 2013) and 1-chloro-2,4-dinitrobenzene for GSTs (Habig et al, 1974)-or relevance to pharmacotherapy (minoxidil, indomethacin, diclofenac, 17b-estradiol, triclosan). Many of the test compounds are substrates for several individual enzymes within the single transferase family: for example, 4-methylumbelliferone (Manevski et al, 2013), 17b-estradiol (Itäaho et al, 2008), diclofenac (King et al, 2001;Kuehl et al, 2005), and indomethacin (Kuehl et al, 2005) are glucuronidated by multiple UGTs; minoxidil is a substrate for several SULTs (Anderson et al, 1998); and 1-chloro-2,4-dinitrobenzene is metabolized by multiple GSTs (Hayes et al, 2005). Since the stratum corneum may severely limit the skin permeation of topically administered drugs, test compounds were directly added to the incubation medium to maximize the tissue exposure.…”

Section: Resultsmentioning

confidence: 99%

“…Although few phase II biotransformation reactions were reported in the skin models previously (Table 2), such as in the case of 4-methylumbelliferone (Jackh et al, 2011;Gotz et al, 2012), minoxidil (Anderson et al, 1998), triclosan (Moss et al, 2000), and p-toluidine Results are presented as the mean value and S.D. To prepare explants with skin after freezing, full-thickness skin from the same donor was snap-frozen in liquid N 2 , kept at -80°C for 7 days, and then thawed at room temperature.…”

Section: Discussionmentioning

confidence: 99%

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Phase II Metabolism in Human Skin: Skin Explants Show Full Coverage for Glucuronidation, Sulfation,N-Acetylation, Catechol Methylation, and Glutathione Conjugation

et al. 2014

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Although skin is the largest organ of the human body, cutaneous drug metabolism is often overlooked, and existing experimental models are insufficiently validated. This proof-of-concept study investigated phase II biotransformation of 11 test substrates in fresh full-thickness human skin explants, a model containing all skin cell types. Results show that skin explants have significant capacity for glucuronidation, sulfation, N-acetylation, catechol methylation, and glutathione conjugation. Novel skin metabolites were identified, including acyl glucuronides of indomethacin and diclofenac, glucuronides of 17b-estradiol, N-acetylprocainamide, and methoxy derivatives of 4-nitrocatechol and 2,3-dihydroxynaphthalene. Measured activities for 10 mM substrate incubations spanned a 1000-fold: from the highest 4.758 pmol·mg skin ·h -1 for 17b-estradiol 17-glucuronidation. Interindividual variability was 1.4-to 13.0-fold, the highest being 4-methylumbelliferone and diclofenac glucuronidation. Reaction rates were generally linear up to 4 hours, although 24-hour incubations enabled detection of metabolites in trace amounts. All reactions were unaffected by the inclusion of cosubstrates, and freezing of the fresh skin led to loss of glucuronidation activity. The predicted whole-skin intrinsic metabolic clearances were significantly lower compared with corresponding whole-liver intrinsic clearances, suggesting a relatively limited contribution of the skin to the body's total systemic phase II enzymemediated metabolic clearance. Nevertheless, the fresh full-thickness skin explants represent a suitable model to study cutaneous phase II metabolism not only in drug elimination but also in toxicity, as formation of acyl glucuronides and sulfate conjugates could play a role in skin adverse reactions.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Phase II Metabolism in Human Skin: Skin Explants Show Full Coverage for Glucuronidation, Sulfation,N-Acetylation, Catechol Methylation, and Glutathione Conjugation

et al. 2014

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“…However, there are a number of studies that demonstrate such capacity ex vivo (see Table 4). Demonstration of metabolism through metabolite identification in cultured skin cells or skin explants provides evidence for N-acetylation (Reilly et al, 2000;Bhaiya et al, 2006), N-hydroxylation (Reilly et al, 2000;Bhaiya et al, 2006), and sulfation (Hamamoto and Mori, 1989;Kudlacek et al, 1995;Anderson et al, 1998).…”

Section: Evidence For the Metabolism Of Drugs In Skin And Skin Cellsmentioning

confidence: 99%

“…Deployment of this drug for the promotion of hair growth led to studies that demonstrated that minoxidil sulfate is the active species for hair follicle stimulation. It is not surprising that studies in skin biopsies and cultured KCs have shown that the cutaneous environment is capable of metabolizing minoxidil to its active sulfate metabolite (Hamamoto and Mori, 1989;Kudlacek et al, 1995;Anderson et al, 1998).…”

Section: Evidence For the Metabolism Of Drugs In Skin And Skin Cellsmentioning

confidence: 99%

Biotransformation of Drugs in Human Skin

Svensson

2008

Drug Metab Dispos

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ABSTRACT:Although it is the largest organ of the human body, skin is often not considered in discussions of drug metabolism. However, there is growing evidence that most common drug-metabolizing enzymes are expressed in the skin. Evidence for expression of cytochromes P450, flavin monooxygenases, glutathione-S-transferases, N-acetyltransferases, and sulfotransferases in human skin and skin cells are presented. Additional discussion is focused on the evidence of actual metabolism of drugs. Finally, the potential clinical implications of metabolism within the skin are discussed briefly.Representing the largest organ in the human body, skin provides an important barrier role in protecting the body from external chemicals and pathogens that would otherwise impair critical functions needed for survival. Comprised of a complex cellular network, skin is capable of many metabolic functions common to visceral organs, including the biotransformation of drugs that penetrate through its most external layer. In addition to being an important target for pharmacotherapy, delivery through the skin is increasingly used as an effective means of delivering drugs to the systemic circulation. It is also evident that biotransformation within the skin may be an essential step to manifesting cutaneous toxicity to certain drugs and chemicals. Hence, an understanding of the capacity and impact of drug biotransformation within skin is an important component in assessing pharmacotherapy directed to or through the cutaneous environment. In the present article, discussion will be limited to evidence for biotransformation of drugs generated specifically in human skin or skin cells. Although many investigations have probed the ability of skin from numerous species to metabolize a variety of environmental chemicals, the focus of the present review is on evidence for metabolism of therapeutic agents. The reader is referred to the recent review of Oesch et al. (2007) for a comparison of xenobiotic-metabolizing enzymes in the skin of various species. Overview of the Structure and Function of SkinExisting as a dynamic and flexible barrier, human skin serves a multifaceted role as the organ with the greatest exposure to the external environment. In addition to providing the primary means for tactile evaluation of the immediate surroundings, skin serves a critical role in thermoregulation of the body. The plethora of infectious diseases with cutaneous manifestations attests to the important sentinel role of skin in protecting the body from bacterial, fungal, and viral pathogens. Although this diversity of function is recognized, it is not surprising that skin is populated by numerous types of specialized cells (see Table 1) that enable dynamic interaction with the internal and external environment. Because studies assessing the role of skin in drug metabolism often use model cells, it is important to begin this review with a brief discussion of skin structure and function.Three identifiable layers comprise human skin: epidermis, dermis, and hypodermi...

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“…Оказалось, что активность сульфотрансферазы в ко-же головы мужчин, реагирующих на введение ми-ноксидила, была выше таковой у мужчин, не реаги-рующих на него. Позже были обнаружены индиви-дуальные различия в активности сульфотрансфераз, содержащихся в коже головы, что коррелировало с их концентрацией в тромбоцитах [26].…”

Section: как это работает?unclassified

Minoxidil: a final judgment or a hope?

Gadzhigoroeva¹

2016

Klin. dermatol. venerol.

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ооо «Институт Красивых волос», Москва, Россия, 105082Миноксидил является базовым препаратом для наружной терапии андрогенетической алопеции у мужчин и женщин. Между тем отношение к миноксидилу неоднозначно как среди пациентов, так и среди врачей. недостаточное понимание этиологии разных форм потери волос, отсутствие ясности в механизмах интеракции миноксидила с клетками-мишенями, в особенности с клетками волосяного фолликула, а также специфичность реакции самих волос на ранних этапах лечения компрометирует действие препарата на волосы и организм человека в целом, ограничивая терапевтические возможности при лечении облысения, снижает комплаентность лечению у пациента. в статье приводится обзор научных исследований о стимулирующих механизмах миноксидила на рост волос, о клинической эффективности и преимуществе использования лекарственной формы препарата в виде пены при андрогенетической алопеции.Ключевые слова: миноксидил, пена миноксидил, андрогенетическая алопеция, лечение. Minoxidil: a final judgment or a hope?A.g. gADzHIgoRoEvA «Institute of nice Hair», Moscow, Russia, 105082Minoxidil is a basic drug for the topical treatment of androgenetic alopecia in males and females. Meanwhile, the attitude of both patients and medical professionals to minoxidil is controversial. Insufficient understanding of the etiology of various forms of hair loss, lack of clear understanding of the mechanisms of interaction between minoxidil and target cells, particularly the hair follicle cells, as well as specific reactions of the hair itself at the early stages of treatment, compromise drug effect on the hair and the entire human body, which results in limited therapeutic potential in treatment of hair loss and reduces patients' compliance. This article provides an overview of the research of stimulatory mechanisms of minoxidil on hair growth, clinical efficacy and benefits of the use of foam-like dosage form of the drug in patients with androgenetic alopecia.

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Sulfation of minoxidil by multiple human cytosolic sulfotransferases

Cited by 64 publications

References 34 publications

Phase II Metabolism in Human Skin: Skin Explants Show Full Coverage for Glucuronidation, Sulfation,N-Acetylation, Catechol Methylation, and Glutathione Conjugation

Phase II Metabolism in Human Skin: Skin Explants Show Full Coverage for Glucuronidation, Sulfation,N-Acetylation, Catechol Methylation, and Glutathione Conjugation

Biotransformation of Drugs in Human Skin

Minoxidil: a final judgment or a hope?

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