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ABSTRACT: Aim: Recent studies have revealed that primary biliary cirrhosis patients with anticentromere antibody (ACA) commonly develop portal hypertension. However, the clinical characteristics of autoimmune hepatitis (AIH) remain uncertain. We investigated the clinical features of patients with AIH seropositive for ACA (ACA-AIH), comparing them with those of patients with AIH seropositive for other immunofluorescent patterns of antinuclear antibodies (ANA) (other-AIH). Methods: AIH was diagnosed on the basis of the scoring system proposed by the International Autoimmune Hepatitis Group. Seropositivity for ACA was determined by a discrete speckled pattern on HEp-2 cells by an immunofluorescent technique. The severity of histological grading and staging was evaluated by the histological activity index (HAI) score. Results: Eight (17%) of 47 patients with AIH had ACA. No significant differences in age, sex, onset pattern of the disease, progression to hepatic failure and relapse rate were present between the ACA-AIH and other-AIH groups. The frequency of concurrent autoimmune diseases in ACA-AIH was significantly higher than that in other-AIH (75% vs 36%, P = 0.0406). Biochemical analysis revealed a significantly lower mean immunoglobulin G (IgG) level than that in other-AIH (2176 +/- 641 vs 3013 +/- 923 mg/dL, P = 0.0150). However, there were no differences in serum alanine aminotransferase levels, titers of ANA, HAI scores or the positive rate of human leukocyte antigen (HLA)-DR4 between the groups. Conclusion: These results suggest that the emergence of ACA is not a distinct entity of AIH, despite its clinical characteristics of a significantly higher frequency of concurrent autoimmune diseases and lower serum IgG levels.
Hepatology Research 08/2010; 40(8):786-92. · 2.20 Impact Factor
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Takashi Himoto,
Seiji Nakai,
Fumihiko Kinekawa,
Hirohito Yoneyama,
Akihiro Deguchi,
Kazutaka Kurokochi,
Tsutomu Masaki,
Shoichi Senda,
Reiji Haba,
Seishiro Watanabe, Mikio Nishioka,
Shigeki Kuriyama
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ABSTRACT: The association between anticentromere antibody (ACA) and hepatitis C virus (HCV) infection remains unclear. We subjected eight patients with HCV-related chronic liver disease (CLD) seropositive for ACA to a battery of clinical and laboratory tests. The patient cohort was dominated by females, and four of the eight (50%) patients had a concomitant autoimmune disease. All of the patients had high titers of ACA (>or=1:320). The histological activity index scores in chronic hepatitis C (CH-C) patients with ACA were significantly higher than those in CH-C patients without antinuclear antibody (ANA) (12.8 +/- 1.8 vs. 8.3 +/- 4.5, P = 0.0372). The frequency of human leukocyte antigen (HLA) DR-8 in patients with HCV-related CLD seropositive for ACA was significantly higher than that in patients with CH-C seronegative for ANA (71 vs. 18%, P = 0.0108). These findings suggest that ACA is induced by chronic HCV infection in association with HLA DR-8, and that CH-C patients with ACA exhibit more severe hepatic fibrosis and inflammation than CH-C patients without ANA.
Digestive Diseases and Sciences 02/2009; 54(2):360-8. · 2.12 Impact Factor
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ABSTRACT: Human alpha-fetoprotein (AFP) from serum of patients with cirrhosis and hepatocellular carcinoma (HCC) was separated into several bands by IEF and by erythroagglutinating phytohemagglutinin (E-PHA) affinity electrophoresis. These AFP bands were directly compared in 2-D IEF and E-PHA affinity electrophoresis. IEF of serum AFP was run in 1% agarose IEF gel with 3% Pharmalyte 4.5-5.4. After IEF, a part of the gel was stained for AFP and another part of the gel corresponding to the area of separated AFP bands was cut in 1 mm x 39 mm along the focused direction and transferred to a trough in 1% agarose gel with 0.3 mg/mL E(4)-PHA for second-dimensional affinity electrophoresis. Separated 2-D AFP spots were visualized by antibody-affinity blotting and identified by combining the systems of Johnson et al.. (Johnson, P. J., Ho, S., Cheng, P., Chan, A. et al.., Cancer 1995, 75, 1663-1668) for AFP-I-+IV and of Taketa et al.. (Taketa, K., Ichikawa, E., Taga, H., Hirai, H., Electrophoresis 1985, 6, 492-497) for AFP-P1-5. AFP-P2, the major AFP glycoform, was composed of AFP-I, AFP+I, and AFP+II; AFP-P3, a nonspecific monosialo-AFP, was composed of AFP+II; AFP-P4, HCC-specific monosialo-AFP, was composed of AFP+II, AFP+III, and AFP+IV; and malignancy-related AFP-P5 was composed of AFP+I and AFP+II. Monosialo-AFP (AFP+II) was recovered in all the glycoforms of AFP-P2, -P3, -P4, and -P5; thus, AFP-P4 is more specific to HCC than monosialylated AFP+II.
Electrophoresis 10/2006; 27(17):3480-7. · 3.30 Impact Factor
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Kazutaka Kurokohchi,
Keiji Arima,
Tsutomu Masaki,
Akiihiro Deguchi,
Seiji Nakai,
Asahiro Morishita,
Hirohito Yoneyama,
Tomohiro Ohgi,
Masahiro Ono,
Akira Yoshitake,
Tsuyoshi Maeta,
Yoshihiro Mori,
Fumikazu Kohi, Mikio Nishioka,
Shigeki Kuriyama
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ABSTRACT: Because the underlying mechanism of hepatocellular damages in autoimmune hepatitis (AIH) still remains unclear, analysis of CD28 and bcl-2 molecules, which are critical for T cell activation and survival, was performed in patients with AIH. The number of CD28(+)CD4(+) peripheral blood mononuclear cells (PBMC) in corticosteroid (CS)-treated patients was comparable to normal control individuals but decreased in untreated AIH patients. In contrast, the number of CD28(+)CD8(+) PBMC was decreased in both CS-treated and untreated AIH patients. Analysis of liver-infiltrating mononuclear cells (LIMC) showed that the number of CD28(+)CD4(+) and CD28(-)CD8(+) LIMC were positively correlated with the histology activity index score. Bcl-2(+)CD4(+) LIMC were observed in the portal area of the liver and the numbers fluctuated with disease activity during the time course after CS administration. By contrast, CD8(+) LIMC were shown not to express bcl-2. Taken collectively, these results suggest that bcl-2(+)CD28(+)CD4(+) and bcl-2(-)CD28(-)CD8(+) cells may play critical and distinct roles in hepatocellular damage in AIH.
Journal of Clinical Immunology 08/2006; 26(4):323-30. · 3.08 Impact Factor
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ABSTRACT: Autoantibodies against tumor-associated antigens (TAAs) such as insulin-like growth factor II mRNA-binding proteins (IMPs), p53, c-myc, and survivin were analyzed in patients with hepatocellular carcinoma (HCC), using recombinant proteins of these antigens. Eight of 86 (9.3%) HCC patients had one or more of these autoantibodies. However, serum alpha-fetoprotein (AFP) levels ranged within normal limits in HCC patients with anti-TAAs except for one case with anti-IMP1. One of the HCC patients had autoantibodies against IMP1, IMP3 and p53 before the diagnosis of HCC. These findings may indicate that anti-TAAs seem to be supplementary serological markers for the diagnosis of HCC in AFP-negative cases and that autoantibodies against IMP1, IMP3 and p53 are candidates for predictive markers of HCC development.
International Journal of Oncology 11/2005; 27(4):1079-85. · 2.40 Impact Factor
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ABSTRACT: Autoantibodies against insulin-like growth factor II mRNA-binding proteins (IMPs) were analyzed in patients with hepatocellular carcinoma (HCC) to elucidate the significance of these autoantibodies. Five of 86 (5.8%) HCC patients had one or more of these autoantibodies. Serum alpha-fetoprotein (AFP) levels ranged within normal limits in HCC patients seropositive for anti-IMPs except for one case. One of HCC patients had anti-IMP1 and anti-IMP3 before the diagnosis of HCC. On the other hand, overexpressions of IMP1 and IMP2 in the tumor tissues were observed in 2 (28.6%) and 3 (42.9%) of 7 HCC tissues, respectively. One HCC patient with IMP1/2-overexpression in the tumor tissue had anti-IMP1/2, while the other HCC patients with overexpressions of IMP1/2 in the tumors did not have anti-IMP1/2. These findings may suggest that autoantibodies against IMPs are produced in an antigen-driven immune system and that anti-IMPs seem to be supplementary serological markers for the diagnosis of HCC in AFP-negative cases or predictive markers of HCC.
International Journal of Oncology 03/2005; 26(2):311-7. · 2.40 Impact Factor
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Yasuhiko Kimura,
Carlo Selmi,
Patrick S C Leung,
Tin K Mao,
Joseph Schauer,
Mitchell Watnik,
Shigeki Kuriyama, Mikio Nishioka,
Aftab A Ansari,
Ross L Coppel,
Pietro Invernizzi,
Mauro Podda,
M Eric Gershwin
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ABSTRACT: Epidemiological data suggest that environmental factors may trigger autoimmunity in genetically susceptible individuals. In primary biliary cirrhosis (PBC), it has been postulated that halogenated xenobiotics can modify self-molecules, facilitating the breakdown of tolerance to mitochondrial antigens. The transport and metabolism of xenobiotics is highly dependent on key genetic polymorphisms that alter enzymatic phenotype. We analyzed genomic DNA from 169 patients with PBC and 225 geographically and sex-matched healthy subjects for polymorphisms of genes coding for cytochromes P450 (CYPs) 2D6 (CYP2D6*4, CYP2D6*3, CYP2D6*5, and CYP2D6*6) and 2E1 (cl/c2), multidrug resistance 1 (MDR1 C3435T) P-glycoprotein, and pregnane X receptor (PXR C-25385T, C8055T, and A7635G). We compared the genotype frequencies in patients and controls and also correlated polymorphisms with PBC severity. The distributions of the studied genotypes did not significantly differ between patients and controls. However, when clinical characteristics of patients with PBC were compared according to genotype, the CYP2E1 c2 allele was associated with signs of more severe disease. In conclusion, genetic polymorphisms of CYP 2D6 and 2E1, PXR, and MDR1 do not appear to play a role in the onset of PBC.
Hepatology 02/2005; 41(1):55-63. · 11.66 Impact Factor
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Yasuhiko Kimura,
Patrick S c Leung,
Thomas P Kenny,
Judy Van De Water, Mikio Nishioka,
Andrew S Giraud,
James Neuberger,
Gordon Benson,
Rashmi Kaul,
Aftab A Ansari,
Ross L Coppel,
M Eric Gershwin
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ABSTRACT: Intestinal trefoil factor (ITF) promotes epithelial cell migration and mucosal restitution during inflammation. We used real-time quantitative PCR, in situ nucleic acid hybridization, and immunohistochemistry to study the expression of the ITF gene and protein expression in the liver of primary biliary cirrhosis (PBC) and controls. There were significantly higher levels of ITF messenger RNA (mRNA) in PBC liver compared with primary sclerosing cholangitis (PSC) (P <.05) or normal controls (P <.001) and also higher in hepatitis C virus (HCV) liver (P <.05) and cryptogenic cirrhosis (P <.01) compared with normal controls. However, only in PBC was there a significant difference between small (interlobular and bile ductules) and large (intrahepatic and septal) bile ducts. Using in situ hybridization, the highest levels of ITF gene expression were localized to the large bile ducts in PBC. This differential expression of ITF was also noted at the protein level. Thus, in PBC, although 92% of large bile ducts expressed the ITF protein, only 2% of small bile ducts (P <.0001) expressed ITF. In contrast, in control livers, 34% of large bile ducts and 13% of small bile ducts expressed ITF. ITF protein is absent in small bile ducts in all stages of PBC. In conclusion, the expression of ITF may play an important role in bile duct damage. In small bile ducts, ITF production in response to damage is absent, making such cells vulnerable to damage and providing a thesis for the selective loss of small, but not large, bile ducts in PBC.
Hepatology 11/2002; 36(5):1227-35. · 11.66 Impact Factor
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ABSTRACT: Cyclin A binds to CDK2 and plays critical roles when cells proliferate; staining for Ki67 can monitor the proliferation. The cyclin A expression pattern remains unclear in colorectal carcinogenesis and remote metastasis, however, and no one has reported on the association of its expression with key clinicopathologic factors in primary cancer. p27(kip1) protein-an extremely important inhibitor of CDK2-seems unchanged as colorectal cancers metastasize to the lymph nodes, a result contrary to that seen in gastric and prostatic cancers. To clarify the role of cyclin A in multistage colorectal neoplasms, cyclin A, CDK2, and Ki67 were immunohistochemically stained in 22 normal mucosa, 9 hyperplastic polyps, 61 adenomas, 197 primary carcinomas, 21 lymph node metastases, and 10 hepatic metastases. To clarify the alteration of p27(kip1) during lymphatic invasion, p27(kip1) was also stained in 21 primary cancers and paired lymph node foci. Situated in nuclei, cyclin A expression gradually increased from mild through moderate to severe dysplasia in adenomas and from normal tissue through hyperplasia to adenoma to early carcinoma. Expression was significantly decreased in the hepatic metastases and in the primary cancers showing venous invasion, deep infiltration, lymph node metastasis, mucinous type, advanced stage, or short postoperative survival time. Elevated cyclin A not only was linked with elevated CDK2 in primary cancers, but also was associated with increased Ki67 in both adenomas and primary carcinomas. Lymph node metastases lost more p27(kip1) than primary foci and hepatic lesions. Thus, dysregulation of cyclin A and its control mechanisms may contribute to colorectal carcinogenesis; abatement of overexpression of cyclin A is associated with hepatic metastasis and cancerous invasion. Loss of p27(kip1) may promote lymph node metastasis.
Human Pathlogy 11/2002; 33(10):1006-15. · 2.88 Impact Factor
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ABSTRACT: Many types of cancer cells widely express cytokeratin 19 (CK19). Clinical investigations have suggested that serum CYFRA 21-1, a fragment of CK19, is one of the most useful tumor markers. In the present study, we hypothesized that released CYFRA 21-1 is closely associated with cellular apoptosis during tumor growth. Apoptosis was induced by tumor necrosis factor-alpha (TNF-alpha) in the HuH-7 hepatocellular carcinoma cell line. Both TNF-alpha-treated and non-treated cells of HuH-7 were simultaneously examined by immunoradiometric assay, annexin-V apoptosis analysis, immunohistochemical staining and colorimetric protease measurement. Levels of CYFRA 21-1 increased significantly in TNF-alpha-treated cells displaying a high percentage of apoptosis, granular-like aggregation of CK19, and elevated activity of caspase-3 in contrast to non-treated cells. Levels of CYFRA 21-1 decreased significantly after caspase-3 was inhibited in TNF-alpha-treated cells. Thus, the release of CYFRA 21-1 may suggest cellular apoptosis in the process of tumor growth.
International Journal of Oncology 09/2002; 21(2):441-5. · 2.40 Impact Factor
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ABSTRACT: We assessed the prevention of hepatic fibrogenesis by a herbal medicine Sho-saiko-to or a carotenoid lycopene in Long-Evans rats with cinnamon coat color (LEC rats). LEC rats were divided into three groups: A (n=40), fed on a basal diet (BD); B (n=25), fed on BD plus 1% Sho-saiko-to; and C (n=40), fed on BD plus 0.005% lycopene. All rats were sacrificed at 76 weeks of age. The liver tissues were stained with Azan--Mallory and alpha-smooth muscle actin (alpha-SMA). The malondialdehyde (MDA) in the liver was measured for the assay of lipoperoxides. The percentage of the total area stained was determined morphometrically. The percentage of the total area involved by fibrosis was 1.35plus minus0.56 in group A, 0.72plus minus0.34 in B (P=0.0020, B vs. A) and 0.78plus minus0.75 in C (P=0.0031, C vs. A). The percentage of the total area that was stained for alpha-SMA was 0.61plus minus0.57 in group A, 0.11plus minus0.05 in B (P=0.0017, B vs. A) and 0.12plus minus0.06 in C (P=0.0021, C vs. A). In group B, MDA in the liver was lower than in group C (P=0.009). In group C, the concentration of iron in the liver was lower than in group A (P=0.0059). In conclusion, Sho-saiko-to suppressed fibrogenesis through reduced generation of lipid peroxides. Hepatic fibrogenesis was also suppressed by lycopene. The mechanisms of this preventive effect of fibrogenesis with Sho-saiko-to and lycopene were suggested to inhibit the stellate cell activity.
Hepatology Research 04/2002; 22(3):196-205. · 2.20 Impact Factor
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ABSTRACT: It has been reported that the cytokeratin 19 (CK19) fragment, CYFRA 21-1, is increased in sera of some hepatocellular carcinoma patients. We hypothesized that CYFRA 21-1 might be released directly from hepatocellular carcinoma. To investigate this mechanism, we evaluated expression of CK19 in 8 human cell lines by immunoradiometric assay, Western blotting, immunohistochemistry, and reverse transcriptase-polymerase chain reaction in Chang liver cells, 2 cholangiocarcinoma cell lines, and 5 hepatocellular carcinoma cell lines. Three of 5 hepatocellular carcinoma cell lines released CYFRA 21-1, synthesized CK19 protein and expressed mRNA for CK19, as observed in 2 cholangiocarcinoma cell lines. In contrast, there was no expression of CK19 in Chang liver cells or 2 of 5 hepatocellular carcinoma cell lines. Analysis of genomic DNA for CK19 demonstrated that exon 1 was not amplified in the 3 cell lines not expressing CK19. However, there were no point mutations within exon 1 and the promoter region of CK19 in hepatocellular carcinoma cell lines. Our present study demonstrates that: i) the expression of CK19 was evident in some human hepatocellular carcinoma cell lines, and ii) the expression of mRNA for CK19 was related to the release of CYFRA 21-1. These results partially clarify the mechanism by which some hepatocellular carcinoma cell lines produce CK19 and others do not.
International Journal of Oncology 02/2002; 20(1):31-7. · 2.40 Impact Factor
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ABSTRACT: OBJECTIVE: Few studies have compared esophageal dysfunction with diabetic neuropathy, and their relationship is not yet clear. The aim of this study was to investigate the relationship between esophageal function and diabetic neuropathy.
The American Journal of Gastroenterology 06/2001; 96(7):2026-2032. · 7.28 Impact Factor
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ABSTRACT: The purpose of the present study is to evaluate the centromeric pattern on human laryngeal tumour (HEp-2) cells by indirect immunofluorescent (IIF) test and to compare their reactivities with a newly developed recombinant centromere protein B enzyme linked immunosorbent assay (CENP-B ELISA) test using sera of antinuclear antibody (ANA)-reactive primary biliary cirrhosis (PBC) patients. Antimitochondrial antibody (AMA) subtypes (PDC-E2, BCOADC-E2, OGDC, protein X, and PDC-E1α) by Western blot were also investigated to see whether they have any effect on the expression of CENP-B reactivities. A centromeric pattern (anticentromere antibody [ACA]) was detected in 11 of 25 (44%) PBC patients whereas CENP-B reactivity was found in 15 (60%) of them. There were some differences in IIF patterns and CENP-B reactivities. One PBC serum with indistinguishable ANA pattern reacted with CENP-B. Eight of 15 (53%) CENP-B reactive patients had other autoimmune-like disorders. Of 181 healthy sera, none was reactive for ACA either by IIF or by ELISA test. There was a correlation between ACA IIF and CENP-B ELISA titres (r= 0.824, P < 0.001). However, no correlation was observed between either CENP-B or AMA reactivities and/or between either autoantibodies or laboratory and histologic indices of PBC. These findings suggest that recombinant CENP-B ELISA appears to be more sensitive in identifying ACA than IIF, underlying its potential value as a screening test for the diagnosis of PBC complicated with other autoimmune-like disorders. The presence of multiple autoantibodies in PBC sera may reflect heterogeneous antigens recognition, and requires further study to identify target antigens at cellular and molecular levels.
Journal of Gastroenterology and Hepatology 07/1995; 10(4):438 - 445. · 2.87 Impact Factor
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ABSTRACT: Cytokine response to viral infection can be of critical importance in the host defense against virus. Interferon (IFN)-γ and
interleukin (IL)-2 have wide ranges of activities in host defense mechanisms. Therefore, these cytokine genes in the liver
were investigated in a series of patients with hepatitis C virus (HCV) infection using a reverse transcribed-polymerase chain
reaction (RT-PCR). Total RNA was purified from liver biopsies, reverse transcribed to cDNA, amplified by specific primers,
and the products were detected by agarose gel and slot blot hybridization. All samples from acute hepatitis (AH; n=4) and
chronic hepatitis patients (CH; n=19) were positive for IFN-γ at varying degrees. AH patients showed strong signals compared
to CH patients, liver cirrhosis (LC; n=12; 72% positive) patients, and hepatocellular carcinoma (HCC; n=21; 19% positive)
patients. IL-2 gene was undetectable in all patients tested. IL-2 receptor (IL-2R) was detectable in AH, CH and LC patients
but not in HCC patients. We conclude that IFN-γ has important roles in the cytokine network that indeed present in the liver
of HCV patients while the presence of IL-2R gene may indicate that the signaling pathway for IL-2 is intact.
Journal of Gastroenterology 04/1993; 28:59-66. · 4.16 Impact Factor
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ABSTRACT: The effects of OK-432 (streptococcal preparation) on murine fulminant hepatitis were investigated. Hepatitis was induced by injection of mouse hepatitis virus type 2 (MHV-2) at a strength of either 1 times 103 or 1 times 104 plaque-forming units (PFU). Mice without OK-432 treatment died within 5 days, whereas mice pre-inoculated with OK-432 showed survival rates of 50% (1 times 103PFU) or 10% (1 times 104PFU) after 60 days. Survival time was not prolonged if OK-432 was injected after MHV-2. Examined histologically, mice not treated with OK-432 showed severe haemorrhagic necrosis of the liver, often panlobular. Treated mice showed less necrosis; the least necrosis was observed in those injected with OK-432 before MHV-2. In those mice injected first with OK-432 and then with 1 times 103PFU of MHV-2 that survived 7 days, autopsy showed a very slight and focal hepatic necrosis, with follicular infiltration by lymphocytes and macrophages. Mitogenic reaction of spleen cells was remarkably less than normal in mice with MHV-2 injection. However, mice injected with OK-432 before MHV-2 (same treatment as mice showing high survival rates) showed relatively high reactivity in comparison with mice not treated with OK-432.
Journal of Gastroenterology and Hepatology 07/1990; 5(4):395 - 401. · 2.87 Impact Factor
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ABSTRACT: Electron microscopic studies of the liver biopsy specimens from two patients with chronic type C hepatitis revealed cytomembranous structures. Cylindrical confronting cisternae were identified for the first time in the cytoplasm of macrophages in the specimen which was taken during α-interferon therapy. Tubuloreticular inclusions were observed in both patients with and without therapy. Although the cytomembranous inclusions are not specific for hepatitis C patients, cylindrical confronting cisternae may be a host response to both large doses of α-interferon and HCV infection.
International Hepatology Communications.
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ABSTRACT: The effects of various antimycotic reagents and some other reagents on a cytochrome P-450-linked monooxygenase system were investigated with respect to the activities of NADPH-ferricyanide reductase. NADPH-cytochrome c reductase of NADPH-adreno-ferredoxin reductase from NADPH to cytochrome c via adreno-ferredoxin, NADPH-cytochrome P-450-phenylisocyanide complex reductase, and the cholesterol side chain cleavage of the cytochrome P-450scc-linked monooxygenase system. No reagents inhibited the NADPH-ferricyanide reductase activity. Only cloconazole inhibited about 50% of NADPH-cytochrome c reductase activity. Cloconazole, econazole, clotrimazole, etomidate and ketoconazole inhibited both NADPH-cytochrome P-450-phenylisocyanide complex reductase and the side chain cleavage activity of cholesterol of the cytochrome P-450scc-linked monooxygenase system. Cloconazole, econazole, etomidate and ketoconazole behaved like non-competitive inhibitors for NADPH-cytochrome P-450-phenylisocyanide reductase activities and their Ki values were 10−4–10−6 M. Cloconazole was a non-competitive inhibitor of NADPH-cytochrome c reductase and its Ki value was 8.3 ×10−4 M. Cloconazole, clotrimazole, econazole, etomidate, ketoconazole and mitotane completely inhibited the side chain cleavage activity of cholesterol.
The Journal of Steroid Biochemistry and Molecular Biology.
