Biphasic hormonal responses to the adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE in human cells

• Published in: Toxicology and applied pharmacology 2010-02, Vol.242 (3), p.281-289
• Main Authors: Asp, Vendela, Ullerås, Erik, Lindström, Veronica, Bergström, Ulrika, Oskarsson, Agneta, Brandt, Ingvar
• Format: Article
• Language: English
• Subjects: Adrenal Cortex - drug effects; Adrenal Cortex - metabolism; Adrenal Gland Neoplasms - drug therapy; ADRENAL HORMONES; Adrenocortical cancer (ACC); Adrenocorticolytic DDT metabolites; ALDEHYDES; ALDOSTERONE; Aldosterone - secretion; ANIMAL CELLS; ANIMALS; Antineoplastic Agents, Hormonal - administration & dosage; Antineoplastic Agents, Hormonal - pharmacology; APOPTOSIS; AROMATICS; Biologi; Biological and medical sciences; Biology; Biphasic responses; CARCINOMAS; Cell and molecular biology; Cell Line; Cell- och molekylärbiologi; CORTICOSTEROIDS; DDT; DDT - metabolism; Dichlorodiphenyl Dichloroethylene - administration & dosage; Dichlorodiphenyl Dichloroethylene - analogs & derivatives; Dichlorodiphenyl Dichloroethylene - pharmacology; DISEASES; Dose-Response Relationship, Drug; Drug Design; DRUGS; Ecotoxicology; Ekotoxikologi; Endocrine disruption; Farmakologi och toxikologi; GLUCOCORTICOIDS; H295R; HORMONES; Humans; HYDROCORTISONE; Hydrocortisone - secretion; HYDROXY COMPOUNDS; INSECTICIDES; KETONES; MALES; MAMMALS; MAN; Medical sciences; MEDICINE; MEN; MESSENGER-RNA; MICE; MINERALOCORTICOIDS; NATURAL SCIENCES; NATURVETENSKAP; NEOPLASMS; NUCLEIC ACIDS; ORGANIC CHLORINE COMPOUNDS; ORGANIC COMPOUNDS; ORGANIC HALOGEN COMPOUNDS; PESTICIDES; Pesticides, fertilizers and other agrochemicals toxicology; Pharmacology and Toxicology; PREGNANES; PRIMATES; RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS; RNA; RNA, Messenger - metabolism; RODENTS; Species Specificity; STEROID HORMONES; Steroidogenesis; STEROIDS; THERAPY; TOXICITY; Toxicology; Toxikologi; VERTEBRATES
• ISSN: 0041-008X; 1096-0333; 1096-0333
• DOI: 10.1016/j.taap.2009.10.018

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.