Ukr.Biochem.J. 2017; Volume 89, Issue 5, Sep-Oct, pp. 5-14

doi: https://doi.org/10.15407/ubj89.05.005

Biochemical mechanism of the o,p’-DDD effect on the adrenal cortex

A. S. Mikosha, O. I. Kovzun

V. P. Komisarenko Institute of Endocrinology and Metabolism, National Academy of Medical Sciences of Ukraine, Kyiv;
e-mail: asmikosha@gmail.com

o,p’-Dichlorodiphenyldichloroethane (o,p’-DDD, mitotane) is used in the treatment of adrenocortical cancer and Cushing’s disease. This medicine induces numerous biochemical changes in the adrenal cortex, as well as disorder in the mitochondrial structure. Therewith, the level of produced corticosteroid hormones is significantly reduced. One of the possible causes can be a decrease in the NADPH level due to inhibition of the activity of its reduction system and increased NADPH consumption during the glutathione reduction catalyzed by glutathione reductase. o,p’-DDD is partially metabolized in the adrenal glands, and   the main metabolite (in terms of quantity) is o,p’-dichlorodiphenylacetic acid. However, attempts to find a physiologically active component among metabolites were unsuccessful. The most pronounced changes caused by o,p’-DDD were found in the mitochondria of the adrenal cortex. The respiration at the level of IV and I complexes is suppressed, the protein content of these complexes decreases. The phospholipid composition of the tissue altered and the concentration of diphosphatidylglycerol, the most important component of mitochondrial membranes, decreased. In our opinion, o,p’-DDD, owing to its high lipophilicity, accumulates in the mitochondria membranes and causes conformational disorder followed by disorder in mitochondrial functions. It was shown that o,p’-DDD acts as an inhibitor of acyl-CoA-cholesterol acyltransferase (ACAT, SOAT1). Therefore, adenocorticocytes accumulate free cholesterol, causing endoplasmic reticulum stress, mitochondrial swelling and caspases activation. Increased apoptosis leads to a decline in adrenal function and to a decrease in weight of adrenal glands.

Keywords: , , , , , , ,


References:

  1. Komisarenko VP, Reznikov AG. Inhibitors of adrenal cortex function. K.: Zdorov’ia, 1972, 374 p. (In Russian).
  2. Nelson AA,  Woodard G. Severe adrenal cortical atrophy (cytotoxic) and hepatic damage produced in dogs by feeding 2,2-bis(parachlorophenyl)-1,1-dichloroethane (DDD or TDE). Arch Pathol (Chic). 1949 Nov;48(5):387-94. PubMed
  3. Kravchenko VI. Effect of o,p’-DDD on biosynthesis of corticosteroids in the adrenal tissue in vitro. Probl Endokrinol (Mosk). 1973 Sep-Oct;19(5):76-9. (In Russian). PubMed
  4. Hart MM, Straw JA. Effect of 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane on adrenocorticotropic hormone-induced steroidogenesis in various preparations in vitro of dog adrenal cortex. Biochem Pharmacol. 1971 Jul;20(7):1679-88. PubMed, CrossRef
  5. Komisarenko VP, Reznikov OH, Mikosha OS. Current concepts of the mechanism of action o,p’-DDD on the adrenal cortex function. Fiziol Zh. 1972 Sep-Oct;18(5):579-84. (In Ukrainian). PubMed
  6. Komissarenko VP, Mestechkina AIa, Mikosha AS. Effect of o,p’-dichlorodiphenyldichloroethane on glutathione reductase activity and on the SH-group content in the adrenals of dogs. Biull Eksp Biol Med. 1974 Jul;78(7):44-6. (In Russian). PubMed
  7. Komissarenko VP, Chelnakova IS, Mikosha AS. Activity of glutathione reductase in the adrenal glands and the liver of dogs after administration O,P-DDD, perthane and ACTH. Probl Endokrinol (Mosk). 1978 Jan-Feb;24(1):95-8. (In Russian). PubMed
  8. Komissarenko VP, Chelnakova IS, Mikosha AS. Effect of O,N’=dichlorodiphenyldichloroethane and pertan in vitro on glutathione reductase activity in the adrenals of dogs and guinea pigs. Biull Eksp Biol Med. 1978 Feb;85(2):159-61. (In Russian). PubMed
  9. Chelnakova IS, Mikosha AS, Todor IN. Analysis of the effect of chloditan on glutathione-S-transferase in the adrenals and liver. Farmakol Toksikol. 1985 Nov-Dec;48(6):104-6. (In Russian). PubMed
  10. Zorich PA, Tronko ND, Mikosha AS. Effect of chloditan on the changes of activity of glutathione transferase, glutathione reductase and glutathione content in the adrenal glands and liver in rats. Fiziol Zh. 1994 Jan-Feb;40(1):86-90. (In Russian). PubMed
  11. Volante M, Terzolo M, Fassnacht M, Rapa I, Germano A, Sbiera S, Daffara F, Sperone P, Scagliotti G, Allolio B, Papotti M, Berruti A. Ribonucleotide reductase large subunit (RRM1) gene expression may predict efficacy of adjuvant mitotane in adrenocortical cancer. Clin Cancer Res. 2012 Jun 15;18(12):3452-61.  PubMed, CrossRef
  12. Millis SZ, Ejadi S, Demeure MJ. Molecular profiling of refractory adrenocortical cancers and predictive biomarkers to therapy. Biomark Cancer. 2015 Dec 17;7:69-76. PubMed, PubMedCentral, CrossRef
  13. Ronchi CL, Sbiera S, Volante M, Steinhauer S, Scott-Wild V, Altieri B, Kroiss M, Bala M, Papotti M, Deutschbein T, Terzolo M, Fassnacht M, Allolio B. CYP2W1 is highly expressed in adrenal glands and is positively associated with the response to mitotane in adrenocortical carcinoma. PLoS One. 2014 Aug 21;9(8):e105855.  PubMed, PubMedCentral, CrossRef
  14. Roca E, Berruti A, Sbiera S, Rapa I, Oneda E, Sperone P, Ronchi CL, Ferrari L, Grisanti S, Germano A, Zaggia B, Scagliotti GV, Fassnacht M, Volante M, Terzolo M, Papotti M. Topoisomerase 2α and thymidylate synthase expression in adrenocortical cancer. Endocr Relat Cancer. 2017 Jul;24(7):299-307.  PubMed, CrossRef
  15. Martz F, Straw JA. The in vitro metabolism of 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane (o,p’-DDD) by dog adrenal mitochondria and metabolite covalent binding to mitochondrial macromolecules: a possible mechanism for the adrenocorticolytic effect. Drug Metab Dispos. 1977 Sep-Oct;5(5):482-6. PubMed
  16. Martz F, Straw JA. Metabolism and covalent binding of 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane (o,p,’-DDD). Correlation between adrenocorticolytic activity and metabolic activation by adrenocortical mitochondria. Drug Metab Dispos. 1980 May-Jun;8(3):127-30. PubMed
  17. Cai W, Counsell RE, Djanegara T, Schteingart DE, Sinsheimer JE, Wotring LL. Metabolic activation and binding of mitotane in adrenal cortex homogenates. J Pharm Sci. 1995 Feb;84(2):134-8. PubMed, CrossRef
  18. Cai W, Counsell RE, Schteingart DE, Sinsheimer JE, Vaz AD, Wotring LL. Adrenal proteins bound by a reactive intermediate of mitotane. Cancer Chemother Pharmacol. 1997;39(6):537-40. PubMed, CrossRef
  19. Hescot S, Paci A, Seck A, Slama A, Viengchareun S, Trabado S, Brailly-Tabard S, Al Ghuzlan A, Young J, Baudin E, Lombès M. The lack of antitumor effects of o,p’DDA excludes its role as an active metabolite of mitotane for adrenocortical carcinoma treatment. Horm Cancer. 2014 Oct;5(5):312-23.  PubMed, PubMedCentral, CrossRef
  20. Gordienko VM, Kozyritskiy VG. Change in the urtrastructure of the dog adrenal cortex following short-term and prolonged administration of o, p’-DDD. Arkh Anat Gistol Embriol. 1973 Jul;65(7):90-5. (In Russian). PubMed
  21. Hart MM, Reagan RL, Adamson RH. The effect of isomers of DDD on the ACTH-induced steroid output, histology and ultrastructure of the dog adrenal cortex. Toxicol Appl Pharmacol. 1973 Jan;24(1):101-13. PubMed, CrossRef
  22. Powers JM, Hennigar GR, Grooms G, Nichols J. Adrenal cortical degeneration and regeneration following administration of DDD. Am J Pathol. 1974 Apr;75(1):181-94. PubMed, PubMedCentral
  23. Poli G, Guasti D, Rapizzi E, Fucci R, Canu L, Bandini A, Cini N, Bani D, Mannelli M, Luconi M. Morphofunctional effects of mitotane on mitochondria in human adrenocortical cancer cells. Endocr Relat Cancer. 2013 Jun 27;20(4):537-50. PubMed, CrossRef
  24. Fang VS. Cytotoxic activity of 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane (mitotane) and its analogs on feminizing adrenal neoplastic cells in culture. Cancer Res. 1979 Jan;39(1):139-45. PubMed
  25. Komisarenko VP, Tiulenev VI, Mikosha AS. Effect of o-p’-DDD on mitochondria respiration in liver and kidney. Ukr Biokhim Zhurn. 1970;42(6):766-9. (In Ukrainian). PubMed
  26. Lin CW, Chang YH, Pu HF. Mitotane exhibits dual effects on steroidogenic enzymes gene transcription under basal and cAMP-stimulating microenvironments in NCI-H295 cells. Toxicology. 2012 Aug 16;298(1-3):14-23.  PubMed, CrossRef
  27. Zsippai A, Szabó DR, Tömböl Z, Szabó PM, Eder K, Pállinger E, Gaillard RC, Patócs A, Tóth S, Falus A, Rácz K, Igaz P. Effects of mitotane on gene expression in the adrenocortical cell line NCI-H295R: a microarray study. Pharmacogenomics. 2012 Sep;13(12):1351-61.  PubMed, CrossRef
  28. Lehmann TP, Wrzesiński T, Jagodziński PP. The effect of mitotane on viability, steroidogenesis and gene expression in NCI‑H295R adrenocortical cells. Mol Med Rep. 2013 Mar;7(3):893-900.  PubMed, CrossRef
  29. Pushkarev VM, Tronko ND, Kostyuchenko NN, Mikosha AS. Effect of o,p’-DDD and Li+ on apoptotic DNA fragmentation in conventionally normal and tumour tissues of human adrenal cortex. Ukr Biokhim Zhurn. 2007 Mar-Apr;79(2):44-9. PubMed
  30. Mikosha AS, Kostyuchenko NN,  Pushkarev VM. In vitro effects of adrenocorticolytic drug, mitotane on the responses of guinea pig adrenal tissue to different K+ concentrations.  Exp Oncol. 1999; 21(1): 64-69.
  31. Hescot S, Slama A, Lombès A, Paci A, Remy H, Leboulleux S, Chadarevian R, Trabado S, Amazit L, Young J, Baudin E, Lombès M. Mitotane alters mitochondrial respiratory chain activity by inducing cytochrome c oxidase defect in human adrenocortical cells. Endocr Relat Cancer. 2013 May 21;20(3):371-81.  PubMed, CrossRef
  32. Doghman-Bouguerra M, Lalli E. The ER-mitochondria couple: In life and death from steroidogenesis to tumorigenesis. Mol Cell Endocrinol. 2017 Feb 5;441:176-184.  PubMed, CrossRef
  33. Marchi S, Patergnani S, Pinton P. The endoplasmic reticulum-mitochondria connection: one touch, multiple functions. Biochim Biophys Acta. 2014 Apr;1837(4):461-9. PubMed, CrossRef
  34. Doghman-Bouguerra M, Granatiero V, Sbiera S, Sbiera I, Lacas-Gervais S, Brau F, Fassnacht M, Rizzuto R, Lalli E. FATE1 antagonizes calcium- and drug-induced apoptosis by uncoupling ER and mitochondria. EMBO Rep. 2016 Sep;17(9):1264-80.  PubMed, PubMedCentral, CrossRef
  35. Wang HP, Pfeiffer DR, Kimura T, Tchen TT. Phospholipids of adrenal cortex mitochondria and the steroid hydroxylases: the lipid-environment of cytochrome P-450. Biochem Biophys Res Commun. 1974 Mar 15;57(1):93-9. PubMed, CrossRef
  36. Mikosha AS, Latyshev NA. Phospholipid composition of human, dog and guinea pig adrenal cortex. Ukr Biokhim Zhurn. 1983 Mar-Apr;55(2):202-6. (In Ukrainian). PubMed
  37. Mikosha AS, Latyshev NA. Action of chloditane on the phospholipid composition of the adrenals in dogs. Farmakol Toksikol. 1983 Jul-Aug;46(4):65-8. (In Russian). PubMed
  38. Paradies G, Paradies V, De Benedictis V, Ruggiero FM, Petrosillo G. Functional role of cardiolipin in mitochondrial bioenergetics. Biochim Biophys Acta. 2014 Apr;1837(4):408-17.  PubMed, CrossRef
  39. Lambeth JD. Cytochrome P-450scc. Cardiolipin as an effector of activity of a mitochondrial cytochrome P-450. J Biol Chem. 1981 May 25;256(10):4757-62. PubMed
  40. Scheidt HA, Haralampiev I, Theisgen S, Schirbel A, Sbiera S, Huster D, Kroiss M, Müller P. The adrenal specific toxicant mitotane directly interacts with lipid membranes and alters membrane properties depending on lipid composition. Mol Cell Endocrinol. 2016 Jun 15;428:68-81.  PubMed, CrossRef
  41. Mikosha AS. In vitro swelling of adrenal mitochondria under influence of o,p’-dichlorodiphenyldichloroethane. Dokl Akad Nauk UkrSSR, ser.B. 1984; (7): 68-70. (In Russian).
  42. Jacobi J, Lang E, Bissinger R, Frauenfeld L, Modicano P, Faggio C, Abed M, Lang F. Stimulation of erythrocyte cell membrane scrambling by mitotane. Cell Physiol Biochem. 2014;33(5):1516-26. PubMed, CrossRef
  43. Tronko ND, Mikosha AS, Pushkarev VM. Mitotane changes some adrenocortical membrane characteristics.  III rd Europ Congress of Endocrinology. Amsterdam 17-22 July 1994.  Eur J Endocr.  Suppl 2, 130: P1.028.
  44. Sbiera S, Leich E, Liebisch G, Sbiera I, Schirbel A, Wiemer L, Matysik S, Eckhardt C, Gardill F, Gehl A, Kendl S, Weigand I, Bala M, Ronchi CL, Deutschbein T, Schmitz G, Rosenwald A, Allolio B, Fassnacht M, Kroiss M. Mitotane Inhibits Sterol-O-Acyl Transferase 1 Triggering Lipid-Mediated Endoplasmic Reticulum Stress and Apoptosis in Adrenocortical Carcinoma Cells. Endocrinology. 2015 Nov;156(11):3895-908. PubMed, CrossRef
  45. Kroiss M, Fassnacht M. Inhibition of cholesterol esterification in the adrenal gland by ATR101/PD132301-2, a promising case of drug repurposing. Endocrinology. 2016 May;157(5):1719-21. PubMed, CrossRef
  46. Cheng Y, Kerppola RE, Kerppola TK. ATR-101 disrupts mitochondrial functions in adrenocortical carcinoma cells and in vivo. Endocr Relat Cancer. 2016 Apr;23(4):1-19.  PubMed, PubMedCentral, CrossRef
  47. LaPensee CR, Mann JE, Rainey WE, Crudo V, Hunt SW 3rd, Hammer GD. ATR-101, a Selective and Potent Inhibitor of Acyl-CoA Acyltransferase 1, Induces Apoptosis in H295R Adrenocortical Cells and in the Adrenal Cortex of Dogs. Endocrinology. 2016 May;157(5):1775-88.  PubMed, CrossRef
  48. Kroiss M, Sbiera S, Kendl S, Kurlbaum M, Fassnacht M. Drug Synergism of Proteasome Inhibitors and Mitotane by Complementary Activation of ER Stress in Adrenocortical Carcinoma Cells. Horm Cancer. 2016 Dec;7(5-6):345-355. PubMed, CrossRef

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License.