THE ROLE OF GLUTATHIONE S-TRANSFERASE-DEPENDENT AND CYTOCHROME P450-DEPENDENT METABOLISM IN THE OLFACTORY TOXICITY OF METHYL-IODIDE IN THE RAT

The aim of this study was to investigate the role of metabolic activat ion in the olfactory toxicity of methyl iodide (MeI). Adult male rats were exposed via nose-only inhalation to 100 ppm Mel for 0-6 h, and no n-protein sulphydryl (NP-SH) concentrations determined in selected tis sues. Depletion of NP-SH occurred in all tissues, but was most marked and rapid in the respiratory epithelium of the nasal cavity and the ki dney. Olfactory, lung and liver NP-SH levels were affected to a lesser extent, and those of the brain declined by only 20-30% over the whole time course. In order to modulate glutathione (GSH) status, animals w ere pretreated with (1) phorone plus L-buthionine sulphoximine (BSO), which depleted NP-SH levels in all the tissues examined, or (2) the is opropyl ester of GSH (IP-GSH), which was shown to replenish NP-SH conc entrations in all tissues except the liver of animals previously admin istered phorone. When animals were pre-treated with phorone plus BSO a nd then exposed to 100 ppm Mel for 2 h, there was a potentiation of th e toxicity of Mel as judged by the clinical observations on the animal s. In contrast, treatment with IP-GSH prior to and during exposure to Mel for 4 h afforded a marked protection to the olfactory epithelium. In order to inhibit cytochromes P450, animals were pre-treated with co balt protoporphyrin IX. This decreased hepatic cytochrome P450 concent rations by >90%, but when animals were then exposed to 100 ppm Mel for 4 h there was no effect on the severity of the olfactory lesion. Thes e results indicate that conjugation of Mel with GSH is a detoxificatio n rather than an activation pathway. Also, there is no major role for cytochrome P450-dependent oxidation in the development of the olfactor y lesion.