Biphasic hormonal responses to the adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE in human cells.
The DDT metabolite 3-methylsulfonyl-DDE (3-MeSO(2)-DDE) has been proposed as a lead compound for an improved adrenocortical carcinoma (ACC) treatment. ACC is a rare malignant disorder with poor prognosis, and the current pharmacological therapy o,p'-DDD (mitotane) has limited efficacy and causes severe adverse effects. 3-MeSO(2)-DDE is bioactivated by cytochrome P450 (CYP) 11B1 in mice and causes formation of irreversibly bound protein adducts, reduced glucocorticoid secretion, and cell death in the adrenal cortex of several animal species. The present study was carried out to assess similarities and differences between mice and humans concerning the adrenocorticolytic effects of 3-MeSO(2)-DDE. The results support previous indications that humans are sensitive to the adrenocorticolytic actions of 3-MeSO(2)-DDE by demonstrating protein adduct formation and cytotoxicity in the human adrenocortical cell line H295R. However, neither the irreversible binding nor the cytotoxicity of 3-MeSO(2)-DDE in H295R cells was inhibited by the CYP11B1 inhibitor etomidate. We also report biphasic responses to 3-MeSO(2)-DDE in cortisol and aldosterone secretion as well as in mRNA levels of the steroidogenic genes StAR, CYP11B1 and CYP11B2. Hormone levels and mRNA levels were increased at lower concentrations of 3-MeSO(2)-DDE, while higher concentrations decreased hormone levels. These biphasic responses were not observed with o,p'-DDD or with the precursor DDT metabolite p,p'-DDE. Based on these results, 3-MeSO(2)-DDE remains a viable lead compound for drug design, although the adrenocorticolytic effects of 3-MeSO(2)-DDE in human cells seem more complex than in murine cells.
Asp
Vendela
V
Department of Environmental Toxicology, Uppsala University, Norbyvägen 18 A, SE-752 36 Uppsala, Sweden.
Ullerås
Erik
E
Lindström
Veronica
V
Bergström
Ulrika
U
Oskarsson
Agneta
A
Brandt
Ingvar
I
D000302:Adrenal Cortex / Q000187:drug effects* / Q000378:metabolism; D000310:Adrenal Gland Neoplasms / Q000188:drug therapy; D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D003634:DDT / Q000378:metabolism*; D003633:Dichlorodiphenyl Dichloroethylene / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D013045:Species Specificity
D018931:Antineoplastic Agents, Hormonal; D012333:RNA, Messenger; D000450:Aldosterone; D003633:Dichlorodiphenyl Dichloroethylene; C055238:1-chloro-4-(2,2-dichloro-1-(4-chlorophenyl)ethenyl)-3-(methylsulfonyl)benzene; D003634:DDT; D006854:Hydrocortisone