Inhibition of human adrenal steroidogenic enzymes in vitro by imidazole drugs including ketoconazole

Ayub, Mohammad; Levell, M. J.

doi:10.1016/0022-4731(89)90384-1

Cited by 52 publications

(31 citation statements)

References 27 publications

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“…37) MIC has been found to attenuate the increase in cerebral blood flow elicited by glutamate. 38) MIC has also been demonstrated to be a plasma membrane H (ϩ) ATPase blocker and it affects the intracellular calcium levels in HL60 cells.…”

Section: Discussionmentioning

confidence: 98%

Inhibitory Effect of Miconazole on Melanogenesis

Mun

Lee

Jeong

et al. 2004

Biological & Pharmaceutical Bulletin

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Miconazole (MIC), a regional antifungal agent, has been used worldwide in the treatment of superficial mycosis. However, the effect of MIC on skin pigmentation is not known. In this study, we investigated the inhibitory effect of MIC on melanogenesis in B16 melanoma cells. Tyrosinase activity and melanin content were dose dependently decreased by MIC as compared with untreated cells. The level of tyrosinase protein expression was reduced with treatment MIC. A decrease in cell proliferation was observed in B16 cells treated with MIC 30 m mM, indicating that the MIC-induced depigmenting effect was caused by inhibition of melanin synthesis and not by destruction of B16 cells. Furthermore, MIC markedly suppressed a a-melanocyte stimulating hormone or forskolin-induced tyrosinase activity in B16 cells. Therefore the depigmenting effect of MIC might be due to the inhibition of tyrosinase activity and tyrosinase expression, which eventually slows melanin biosynthesis. These results indicate that MIC may be a useful inhibitor of melanogenesis in B16 cells and suggest that it may have beneficial effects in the treatment of hyperpigmentation disorders such as ephelis and melasma.

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Section: Discussionmentioning

confidence: 98%

Inhibitory Effect of Miconazole on Melanogenesis

Mun

Lee

Jeong

et al. 2004

Biological & Pharmaceutical Bulletin

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“…Ayub and Levell (51)(52)(53)(54) found that human CYP19 was inhibited strongly by econazole, tioconazole, bifoconazole, miconazole, isoconazole, and clotrimazole (IC 50 , 0.25 to 0.67 M), whereas ketoconazole was less potent (IC 50 , 7.3 M), and CYP17 was inhibited by azole antifungals (IC 50 , 0.6 to 4 M). In comparison, prochloraz, propiconazole, and triadimenol inhibited CYP19, with IC 50 s of 0.04, 6.5, and 21 M, respectively (55), indicating that agricultural azoles have the general ability to inhibit the P450 enzymes in steroidogenesis, albeit with different potencies.…”

Section: Discussionmentioning

confidence: 99%

Azole Affinity of Sterol 14α-Demethylase (CYP51) Enzymes from Candida albicans and Homo sapiens

Warrilow

Parker

Kelly

et al. 2013

Antimicrob Agents Chemother

130

115

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Candida albicans CYP51 (CaCYP51) (Erg11), full-length Homo sapiens CYP51 (HsCYP51), and truncated ⌬60HsCYP51 were expressed in Escherichia coli and purified to homogeneity. CaCYP51 and both HsCYP51 enzymes bound lanosterol (K s , 14 to 18 M) and catalyzed the 14␣-demethylation of lanosterol using Homo sapiens cytochrome P450 reductase and NADPH as redox partners. Both HsCYP51 enzymes bound clotrimazole, itraconazole, and ketoconazole tightly (dissociation constants [K d s], 42 to 131 nM) but bound fluconazole (K d , ϳ30,500 nM) and voriconazole (K d , ϳ2,300 nM) weakly, whereas CaCYP51 bound all five medical azole drugs tightly (K d s, 10 to 56 nM). Selectivity for CaCYP51 over HsCYP51 ranged from 2-fold (clotrimazole) to 540-fold (fluconazole) among the medical azoles. In contrast, selectivity for CaCYP51 over ⌬60HsCYP51 with agricultural azoles ranged from 3-fold (tebuconazole) to 9-fold (propiconazole). Prothioconazole bound extremely weakly to CaCYP51 and ⌬60HsCYP51, producing atypical type I UV-visible difference spectra (K d s, 6,100 and 910 nM, respectively), indicating that binding was not accomplished through direct coordination with the heme ferric ion. Prothioconazole-desthio (the intracellular derivative of prothioconazole) bound tightly to both CaCYP51 and ⌬60HsCYP51 (K d , ϳ40 nM). These differences in binding affinities were reflected in the observed 50% inhibitory concentration (IC 50 ) values, which were 9-to 2,000-fold higher for ⌬60HsCYP51 than for CaCYP51, with the exception of tebuconazole, which strongly inhibited both CYP51 enzymes. In contrast, prothioconazole weakly inhibited CaCYP51 (IC 50 , ϳ150 M) and did not significantly inhibit ⌬60HsCYP51. Sterol 14␣-demethylase (CYP51) is an ancestral activity of the cytochrome P450 superfamily and is required for ergosterol biosynthesis in fungi and cholesterol biosynthesis in mammals (1). Fungal CYP51 (Erg11) is the main target for therapeutic azole antifungal drugs and agricultural azole fungicides. This has led to the development of azole inhibitors that are selective for the fungal CYP51 enzyme over the human homolog and are commonly used to treat fungal infections, including those caused by Candida albicans and Aspergillus fumigatus (2-4). Agricultural azoles, however, were developed primarily for selectivity against the fungal CYP51 over the plant homolog. The mode of action of azole antifungals involves the nucleophilic nitrogen of the azole heterocyclic ring directly coordinating as the sixth ligand of the heme ferric ion and the azole drug side chains interacting with the CYP51 polypeptide structure (5).Many yeasts and fungi that are causative agents of clinical infections, such as Candida species and Aspergillus species, are also present in the general environment and are exposed to the selective pressure of agricultural azoles in the field. This has led to concerns that azole-resistant strains of yeasts and fungi responsible for clinical infections are emerging due to the use of agricultural azole fungicides on crops raising azole tole...

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“…The imidazole moiety in histamine and in a large number of drug classes interacts with P450 enzymes to yield type II binding spectra, due to the formation of a ferrihaemochrome (Testa & Jenner, 1981;Feldman, 1986;Murray, 1987;Ayub & Levell, 1989 for a second reaction (Lennard et al, 1986;Morris et al, 1989). binding sites in microsomes from several tissues and the potency to inhibit platelet aggregation (Brandes et al, 1990;1991).…”

Section: Discussionmentioning

confidence: 99%

H₃ receptor antagonist, thioperamide, inhibits adrenal steroidogenesis and histamine binding to adrenocortical microsomes and binds to cytochrome P450

LaBella

Queen

Glavin

et al. 1992

British J Pharmacology

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Inhibition of human adrenal steroidogenic enzymes in vitro by imidazole drugs including ketoconazole

Cited by 52 publications

References 27 publications

Inhibitory Effect of Miconazole on Melanogenesis

Inhibitory Effect of Miconazole on Melanogenesis

Azole Affinity of Sterol 14α-Demethylase (CYP51) Enzymes from Candida albicans and Homo sapiens

H₃ receptor antagonist, thioperamide, inhibits adrenal steroidogenesis and histamine binding to adrenocortical microsomes and binds to cytochrome P450

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Inhibition of human adrenal steroidogenic enzymes in vitro by imidazole drugs including ketoconazole

Cited by 52 publications

References 27 publications

Inhibitory Effect of Miconazole on Melanogenesis

Inhibitory Effect of Miconazole on Melanogenesis

Azole Affinity of Sterol 14α-Demethylase (CYP51) Enzymes from Candida albicans and Homo sapiens

H3 receptor antagonist, thioperamide, inhibits adrenal steroidogenesis and histamine binding to adrenocortical microsomes and binds to cytochrome P450

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H₃ receptor antagonist, thioperamide, inhibits adrenal steroidogenesis and histamine binding to adrenocortical microsomes and binds to cytochrome P450