Methemoglobin Forming Effect of Dimethyl Trisulfide in Mice

Abstract

Dimethyl trisulfide (DMTS) is a natural organic trisulfide that has been patented as a promising antidotal candidate against cyanide (CN). The primary mode of action of DMTS is as a sulfur donor that enables the conversion of CN to thiocyanate. Recently, it was discovered that DMTS is capable of oxidizing hemoglobin (Hb) to methemoglobin (MetHb) in vitro. The goal of these experiments was to measure the extent of DMTS-induced MetHb formation in vivo. In these experiments, intramuscular (IM) injections of formulated DMTS were administered to mice. Following the IM injection, blood was drawn and analyzed for MetHb using a rapid spectrophotometric method. Methemoglobin levels peaked in a dose-dependent manner between 20 and 30 min., and then began dropping. The highest MetHb levels measured for the 50, 100, 200 and 250 mg/kg doses of DMTS were respectively 3.28, 6.12, 9.69, and 10.76% MetHb. These experiments provide the first experimental evidence that IM administered DMTS generates MetHb in vivo and provide additional evidence for the presence of a secondary therapeutic pathway for DMTS - CN scavenging by DMTS-generated MetHb.

KEYWORDS:

• Antidote
• cyanide (CN)
• dimethyl trisulfide (DMTS)
• hemoglobin (Hb)
• methemoglobin (MetHb)

Acknowledgments

The authors would like to thank Dr. Afshin Ebrahimpour (Sam Houston University, Huntsville, TX, USA), for his help in the in vivo procedures, Dr. Gabriella Arato (Kenessey Albert Hospital, Balassagyarmat, Hungary) and Maria Gondor Tamasne Toth (Grof Tisza Istvan Hospital, Berettyoujfalu, Hungary) for providing information about the MetHb assay.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Funding

This study was supported by the National Institutes of Health (NIH) CounterACT Program, the NIH Office of the Director, and the NIH National Institute of Allergy and Infectious Diseases, Department of Defense Interagency Agreement [AOD16026-001-0000/A120-B.P2016-01], and the Robert A. Welch Foundation [X-0011] at Sam Houston State University, Huntsville, TX, USA.