TISSUE-DEPENDENT INDUCTION OF HEME OXYGENASE-1 AND METALLOTHIONEIN-1/2 BY METHYL METHANESULFONATE

• Published in: Journal of toxicological sciences 2003, Vol.28(3), pp.181-189
• Main Authors: ASHINO, Takashi, OZAWA, Shigenari, NUMAZAWA, Satoshi, YOSHIDA, Takemi
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Heme Oxygenase (Decyclizing) - biosynthesis; Heme Oxygenase (Decyclizing) - genetics; Heme Oxygenase-1; Kidney - drug effects; Kidney - enzymology; Liver - drug effects; Liver - enzymology; Male; Metallothionein - biosynthesis; Metallothionein - genetics; Metallothionein-1/2; Methyl methanesulfonate; Methyl Methanesulfonate - toxicity; Microsomes - drug effects; Microsomes - enzymology; Mutagens - toxicity; Rat; Rats; Rats, Sprague-Dawley; RNA, Messenger - metabolism; Testis - drug effects; Testis - enzymology
• ISSN: 0388-1350; 1880-3989
• DOI: 10.2131/jts.28.181

Methyl methanesulfonate (MMS), a methylating agent, is known to be a genotoxicant in testis. The purpose of this study was to investigate roles of oxidative stress-responsive proteins, heme oxygenase-1 (HO-1) and metallothionein-1/2 (MT-1/2), in genotoxicity of MMS. Cadmium, a potent genotoxicity inducer, induced HO-1 and MT-1/2 in rat livers and kidneys. Then we comparatively investigated MMS-induced HO-1 and MT-1/2 in rat livers, kidneys and testes. We found that a single administration of MMS (40 mg/kg) resulted in the induction of MT-1/2 mRNA in the liver, but not HO-1 mRNA, reaching maximum level at 6 hr and returning to the control levels by 24 hr. Interestingly, MMS induced both HO-1 and MT-1/2 mRNAs in the kidney. In contrast, MMS induced HO-1 mRNA, but not MT-1/2 mRNA in the testis. Since HO-1 and MT-1/2 have been recognized to respond to various oxidative stimuli, we further examined the inducing effect of MMS on these two proteins. MMS at dosages of 20 to 40 mg/kg for 2 consecutive weeks induced HO-1 mRNA (123 to 187% of the control) and protein (274 to 404% of the control) in rat testes. However, MT-1/2 mRNA was not induced by MMS administration, although a high level of expression was observed in comparison with the liver and kidney. These findings suggest that MMS induces HO-1 and/or MT-1/2 mRNA and its protein tissue-dependently, and the heme catabolites by HO-1 in the testis may contribute in some manner to its genotoxicity.