Ketoconazole as a Possible Universal Inhibitor of Cytochrome P-450 Dependent Enzymes: Its Mode of Inhibition

Higashi, Yotsuo; Omura, Masako; Suzuki, Kunihiro; Itoh, Hiroshi; Oshima, Hiroyuki

doi:10.1507/endocrj1954.34.105

Cited by 42 publications

(19 citation statements)

References 25 publications

(7 reference statements)

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“…To determine whether a testis-specific CYP enzyme could be responsible for the lack of Stra8 expression in embryonic testes, we assayed Stra8 expression in gonads cultured in the presence of ketoconazole, a potent but nonspecific CYP inhibitor (29,30). As expected, testes dissected at E12.5 and cultured for 2 days in control medium did not express Stra8 (Fig.…”

Section: Cyp-mediated Metabolism Of Ra Prevents Stra8 Expression In Ementioning

confidence: 67%

Retinoic acid regulates sex-specific timing of meiotic initiation in mice

Koubova

Menke

Zhou³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

843

976

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In mammals, meiosis is initiated at different time points in males and females, but the mechanism underlying this difference is unknown. Female germ cells begin meiosis during embryogenesis. In males, embryonic germ cells undergo G 0 ͞G 1 mitotic cell cycle arrest, and meiosis begins after birth. In mice, the Stimulated by Retinoic Acid Gene 8 (Stra8) has been found to be required for the transition into meiosis in both female and male germ cells. Stra8 is expressed in embryonic ovaries just before meiotic initiation, whereas its expression in testes is first detected after birth. Here we examine the mechanism underlying the sex-specific timing of Stra8 expression and meiotic initiation in mice. Our work shows that signaling by retinoic acid (RA), an active derivative of vitamin A, is required for Stra8 expression and thereby meiotic initiation in embryonic ovaries. We also discovered that RA is sufficient to induce Stra8 expression in embryonic testes and in vitamin Adeficient adult testes in vivo. Finally, our results show that cytochrome p450 (CYP)-mediated RA metabolism prevents premature Stra8 expression in embryonic testes. Treatment with an inhibitor specific to RA-metabolizing enzymes indicates that a cytochrome p450 from the 26 family (CYP26) is responsible for delaying Stra8 expression in embryonic testes. Sex-specific regulation of RA signaling thus plays an essential role in meiotic initiation in embryonic ovaries and precludes its occurrence in embryonic testes. Because RA signaling regulates Stra8 expression in both embryonic ovaries and adult testes, this portion of the meiotic initiation pathway may be identical in both sexes.sex determination

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Section: Cyp-mediated Metabolism Of Ra Prevents Stra8 Expression In Ementioning

confidence: 67%

Retinoic acid regulates sex-specific timing of meiotic initiation in mice

Koubova

Menke

Zhou³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

843

976

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“…125 I]IPX (29 Ϯ 1 and 117 Ϯ 7 fmol/mg protein, respectively) was also inhibited in a dose-dependent manner by ketoconazole, a imidazole-containing broad-spectrum cytochrome P450 inhibitor (Higashi et al, 1987) (Fig. 1B) (Fig.…”

Section: Resultsmentioning

confidence: 94%

“…Our binding data strongly support this hypothesis. First, the non-H 3 R binding was fully displaced by ketoconazole, an imidazole-containing broad-spectrum cytochrome P450 inhibitor, with a consistent submicromolar potency (Higashi et al, 1987;Yang et al, 2002). Second, it was also fully inhibited by the three imidazole-containing compounds, ciproxifan, thioperamide, and clobenpropit, with submicromolar potencies similar to those found at adrenal P450 enzymes (LaBella et al, 1992;Yang et al, 2002) but two orders of magnitude lower than their affinities at rat H 3 Rs (Stark et al, 2001).…”

Section: Discussionmentioning

confidence: 90%

Autoregulation of McA-RH7777 Hepatoma Cell Proliferation by Histamine H₃Receptors

Davenas¹,

Rouleau²,

Morisset-Lopez³

et al. 2008

J Pharmacol Exp Ther

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Previous studies have suggested that histamine (HA) acts as an autocrine growth factor. We have explored the modulation of cell proliferation by HA using McA-RH7777 hepatoma cells. High L-histidine decarboxylase (HDC) expression and HA synthesis were found in McA-RH7777 cells. Whereas extracellular HA reached submicromolar concentrations, intracellular levels were very low, indicating that HA was secreted by the cells.McA-RH7777 cells also express H 3 -receptor (H 3 R) transcripts and proteins. Reverse transcriptase-polymerase chain reaction analysis detected only transcripts for the long isoform. Immunocytochemistry performed with a selective H 3 R antibody showed that most cells were immunoreactive. H 3 R binding sites (B max ϳ30 fmol/mg protein) were identified when [125 I] iodoproxyfan binding was displaced by the agonist imetit. High-affinity binding also occurred at cytochrome P450 enzymes. This binding was not inhibited by HA, H 3 R agonists, or by a nonimidazole H 3 R antagonist but was displaced by imidazole H 3 R antagonists or by ketoconazole, a imidazolecontaining cytochrome inhibitor. HA inhibited proliferation of McA-RH7777 hepatoma cells. The absence of uptake system, its much higher potency at H 3 Rs, and its low intracellular levels suggested that HA interacted with H 3 Rs rather than cytochromes. In agreement, both imidazole H 3 R antagonists, a nonimidazole H 3 R antagonist, and the HDC inhibitor ␣-monofluoromethyl histidine increased cell proliferation (up to ϳ60%), revealing a H 3 R-mediated inhibition by endogenous HA. Moreover, exogenous HA inhibited the increase induced by ␣-FMH or H 3 R antagonists with a nanomolar potency. In conclusion, our findings show that HA regulates proliferation of McA-RH7777 hepatoma cells by interacting with autoinhibitory H 3 Rs.

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“…Alternatively, hydroxylation of bile acids by the hepatocytes was inhibited by simultaneous incubation of bile acids with 10 pM ketoconazole over a similar period of time in a separate set of experiments, as described above. The latter substance has been shown to effectively inhibit hydroxylation reactions catalyzed by NADPH-cytochrome-P-450-dependent monooxygenases [31], among them cholesterol 7u-hydroxylase (inhibits up to 94% at 10 pM) [25]. Culturing of cells in the presence of ketaconazole thus made assessment of the effects of bile acids on cholesterol 7a-hydroxylase activity impossible, but had no adverse effect on the expression of cholesterol 7a-hydroxylase mRNA levels.…”

Section: Methodsmentioning

confidence: 99%

Structural Aspects of Bile Acids Involved in the Regulation of Cholesterol 7alpha-Hydroxylase and Sterol 27-Hydroxylase

Twisk¹,

Hoekman²,

Muller³

et al. 1995

Eur J Biochem

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We have recently reported that coordinate down-regulation of cholesterol 7a-hydroxylase and sterol 27-hydroxylase by bile acids results in suppression of bile acid synthesis in cultured rat hepatocytes [Twisk, J., De Wit, E. & Princen, H. M. G. (1995) Biochem. J. 305, 505-5111. In the current study, we have assessed the effects of a large group of different bile acids, both naturally occurring and synthetic, on these two key enzymes, to elucidate structural features which render bile acids potent as regulators of bile acid synthesis.Addition of 50 pM deoxycholate or cholate, two relatively hydrophobic bile acids, to the culture medium of hepatocytes resulted in strong suppression of cholesterol 7a-hydroxylase (suppression of 75 % and 88 %, respectively) and sterol 27-hydroxylase activity (suppression of 76 % and 72%, respectively). These effects were also reflected in the mRNA levels and the transcriptional activities of the two enzymes, showing a parallel suppression of both parameters in response to cholate (suppression of 78% and 43% for cholesterol 7a-hydroxylase mRNA and transcription, respectively, and suppression of 76 % and 42 % for sterol 27-hydroxylase mRNA and transcription, respectively). In contrast, no effects were observed with the two hydrophilic bile acids, P-muricholate and ursocholate. Transient expression analysis in cultured rat hepatocytes, using a promoter-reporter construct containing the proximal part of the cholesterol 7a-hydroxylase promoter, demonstrated a reduction of transcriptional activity by cholate (reduction of 72 %), but not by ursocholate.Assessment of the effects of 27 different bile acids, varying in the number, position and orientation (cxlp, of hydroxyl groups on the steroid nucleus of the molecule, on cholesterol 7a-hydroxylase mRNA showed only a moderate correlation with the hydrophobicity index of the bile acid involved (r = 0.61 ; P < 0.0001). Analysis of the three-dimensional structure of a number of these bile acids suggests that hydroxyl groups situated in close proximity to each other within the molecule, creating a hydrophilic environment, as in the case of cholate, may be a prerequisite for a strong inhibitory potency. Deviation from this situation leads to a markedly lesser effect on suppression of cholesterol 7a-hydroxylase and sterol 27-hydroxylase.

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Ketoconazole as a Possible Universal Inhibitor of Cytochrome P-450 Dependent Enzymes: Its Mode of Inhibition

Abstract: Modes of inhibition and

Cited by 42 publications

References 25 publications

Retinoic acid regulates sex-specific timing of meiotic initiation in mice

Retinoic acid regulates sex-specific timing of meiotic initiation in mice

Autoregulation of McA-RH7777 Hepatoma Cell Proliferation by Histamine H₃Receptors

Structural Aspects of Bile Acids Involved in the Regulation of Cholesterol 7alpha-Hydroxylase and Sterol 27-Hydroxylase

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Ketoconazole as a Possible Universal Inhibitor of Cytochrome P-450 Dependent Enzymes: Its Mode of Inhibition

Abstract: Modes of inhibition and

Cited by 42 publications

References 25 publications

Retinoic acid regulates sex-specific timing of meiotic initiation in mice

Retinoic acid regulates sex-specific timing of meiotic initiation in mice

Autoregulation of McA-RH7777 Hepatoma Cell Proliferation by Histamine H3Receptors

Structural Aspects of Bile Acids Involved in the Regulation of Cholesterol 7alpha-Hydroxylase and Sterol 27-Hydroxylase

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Product

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Autoregulation of McA-RH7777 Hepatoma Cell Proliferation by Histamine H₃Receptors