Effects of 3-MeSO2-DDE and some CYP inhibitors on glucocorticoid steroidogenesis in the H295R human adrenocortical carcinoma cell line.
The formation of steroids in the H295R human adrenocortical carcinoma cell line was analysed by HPLC or RIA, and based on these data the apparent catalytic activities of CYP11A, CYP17, CYP21 and CYP11B1 in this cell line were calculated. The environmental pollutant 3-methylsulfonyl-DDE (3-MeSO2-DDE) and the cytochrome P450 (CYP) inhibitors ketoconazole, metyrapone and aminoglutethimide were studied for their effects on the steroid formation. Metyrapone (IC50) of 1 microM) and 3-MeSO2-DDE (10 microM: 66 +/- 10% of control) were found to inhibit the apparent CYP11B1 activity. Ketoconazole inhibited all enzymes examined with the greatest effects on CYP11B1 (IC50) of 2.5 microM). Aminoglutethimide was examined only for effects on CYP11A activity and was shown to inhibit pregnenolone formation (20 microM: 61 +/- 4% of control). The possibility of studying all CYP enzymes in the corticosteroidogenesis makes this cell line a valuable test system to examine effects of chemicals, such as suspected endocrine disruptors, on the human glucocorticoid hormone synthesis. The inhibition of cortisol formation by 3-MeSO2-DDE supports an interaction with the active site of CYP11B1, as previously reported in mouse adrenocortical Y1 cells. In mice, this interaction led to metabolic activation and a high adrenotoxicity of 3-MeSO2-DDE. Therefore studies on the adrenotoxicity of 3-MeSO2-DDE in humans are needed.
Johansson
M K
MK
Department of Environmental Toxicology, Uppsala University, Norbyv. 18A, SE-752 36 Uppsala, Sweden. maria.johansson@ebc.uu.se
Sanderson
J T
JT
Lund
B-O
BO
D000306:Adrenal Cortex Neoplasms / Q000378:metabolism*; D000616:Aminoglutethimide / Q000494:pharmacology; D002277:Carcinoma / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D005576:Colforsin / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003633:Dichlorodiphenyl Dichloroethylene / Q000031:analogs & derivatives* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004785:Environmental Pollutants / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006854:Hydrocortisone / Q000096:biosynthesis*; D007654:Ketoconazole / Q000494:pharmacology; D008797:Metyrapone / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D065607:Cytochrome P-450 Enzyme Inhibitors; D004338:Drug Combinations; D004785:Environmental Pollutants; D004791:Enzyme Inhibitors; D000616:Aminoglutethimide; D005576:Colforsin; D003633:Dichlorodiphenyl Dichloroethylene; C055238:1-chloro-4-(2,2-dichloro-1-(4-chlorophenyl)ethenyl)-3-(methylsulfonyl)benzene; D007654:Ketoconazole; D006854:Hydrocortisone; D008797:Metyrapone