Effects of combined treatment of α-tocopherol, l-ascorbic acid, selenium and zinc on bleomycin, etoposide and cisplatin-induced alterations in testosterone synthesis pathway in rats

• Published in: Cancer chemotherapy and pharmacology Vol. 74; no. 6; pp. 1175 - 1189
• Main Author: Kilarkaje, Narayana
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-12-2014; Springer
• Subjects: alpha-Tocopherol - administration & dosage; alpha-Tocopherol - pharmacology; Animals; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - toxicity; Antioxidants - administration & dosage; Antioxidants - pharmacology; Ascorbic Acid - administration & dosage; Ascorbic Acid - pharmacology; Biological and medical sciences; Bleomycin - administration & dosage; Blotting, Western; Cancer Research; Cisplatin - administration & dosage; Dose-Response Relationship, Drug; Down-Regulation - drug effects; Drug Therapy, Combination; Etoposide - administration & dosage; Male; Medical sciences; Medicine; Medicine & Public Health; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Rats; Rats, Sprague-Dawley; Selenium - administration & dosage; Selenium - pharmacology; Testosterone - biosynthesis; Time Factors; Up-Regulation - drug effects; Zinc - administration & dosage; Zinc - pharmacology; Antioxidants; Anticancer drugs; Testosterone deficiency; Testicular dysfunction; Testosterone synthesis; Antineoplastic agent; Ascorbic acid; Peptides; Rat; Vitamin; Podophyllotoxin derivatives; α-Tocopherol; Testicle; Isomerases; Bleomycin; Glycopeptide; Testicular hormone; Selenium; Antimitotic; Platinum II Complexes; Drug; DNA topoisomerase (ATP-hydrolysing); Androgen; Enzyme; Deficiency; Rodentia; Enzyme inhibitor; Etoposide; Topoisomerase II inhibitor; Antioxidant; Male genital system; Cisplatin; Zinc; Micronutrient; Testosterone; Alkylating agent; Vertebrata; Mammalia; Dysfunction; Animal; Combined treatment; Sex steroid hormone
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-014-2592-8

Purpose
To investigate the effects of therapeutically relevant dose levels of bleomycin, etoposide and cisplatin (BEP) on testicular steroidogenic enzymes, and possible protective effects of an antioxidant cocktail (AC).
Methods
Adult Sprague–Dawley rats received BEP with or without the AC (α-tocopherol,
l
-ascorbic acid, selenium and zinc) for either (a) 4 days (short term; 1.5, 15 and 3 mg/kg), or (b) three cycles of 21 days each (0.75, 7.5 and 1.5 mg/kg), or (c) the three cycles with a 63-day recovery period. The expression of steroidogenic enzymes were measured in the testes by Western blotting and immunofluorescent labeling.
Results
The short-term BEP exposure resulted in a decrease in scavenger receptor class-B1 and an increase in luteinizing hormone receptor (LHR). The AC with or without BEP has increased the levels of LHR, 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-HSD, but without significant changes in testosterone levels. The three cycles of BEP up-regulated the expression of steroidogenic acute regulatory protein (StAR) and down-regulated that of cholesterol side chain cleavage enzyme (P450scc), cytochrome p450 17A1 (Cyp17A1, recovered by the AC) and 17β-HSD, associated with significant reduction in testosterone levels. The three cycles with the recovery time led to decreases in LHR, StAR, P450scc and Cyp17A1 and increases in 3β-HSD and 17β-HSD. The AC did not enhance the recovery of the enzyme levels.
Conclusion
The three cycles of BEP treatment inhibit the testosterone synthesis pathway even after the recovery time. The AC recovers the effects of BEP chemotherapy on a few steroidogenic enzymes.