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

Journal Article · Mon Feb 01 00:00:00 EST 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2009.10.018· OSTI ID:21344850

Asp, Vendela ^[1]; Ulleras, Erik ^[2]; Lindstroem, Veronica; Bergstroem, Ulrika ^[1]; Oskarsson, Agneta ^[2]; Brandt, Ingvar ^[1]

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1. Department of Environmental Toxicology, Uppsala University, Norbyvaegen 18 A, SE-752 36 Uppsala (Sweden)
2. Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala (Sweden)

The DDT metabolite 3-methylsulfonyl-DDE (3-MeSO{sub 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{sub 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{sub 2}-DDE. The results support previous indications that humans are sensitive to the adrenocorticolytic actions of 3-MeSO{sub 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{sub 2}-DDE in H295R cells was inhibited by the CYP11B1 inhibitor etomidate. We also report biphasic responses to 3-MeSO{sub 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{sub 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{sub 2}-DDE remains a viable lead compound for drug design, although the adrenocorticolytic effects of 3-MeSO{sub 2}-DDE in human cells seem more complex than in murine cells.

• OSTI ID: 21344850
• Journal Information: Toxicology and Applied Pharmacology, Vol. 242, Issue 3; Other Information: DOI: 10.1016/j.taap.2009.10.018; PII: S0041-008X(09)00456-6; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

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63 RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS
ALDOSTERONE
ANIMAL CELLS
APOPTOSIS
CARCINOMAS
DDT
DRUGS
HYDROCORTISONE
MEN
MESSENGER-RNA
MICE
THERAPY
TOXICITY
ADRENAL HORMONES
ALDEHYDES
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CORTICOSTEROIDS
DISEASES
GLUCOCORTICOIDS
HORMONES
HYDROXY COMPOUNDS
INSECTICIDES
KETONES
MALES
MAMMALS
MAN
MEDICINE
MINERALOCORTICOIDS
NEOPLASMS
NUCLEIC ACIDS
ORGANIC CHLORINE COMPOUNDS
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
PESTICIDES
PREGNANES
PRIMATES
RNA
RODENTS
STEROID HORMONES
STEROIDS
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