The role of glutathione S-transferase- 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 activation in the olfactory toxicity of methyl iodide (MeI). Adult male rats were exposed via nose-only inhalation to 100 ppm MeI for 0-6 h, and non-protein sulphydryl (NP-SH) concentrations determined in selected tissues. Depletion of NP-SH occurred in all tissues, but was most marked and rapid in the respiratory epithelium of the nasal cavity and the kidney. 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 were pre-treated with (1) phorone plus L-buthionine sulphoximine (BSO), which depleted NP-SH levels in all the tissues examined, or (2) the isopropyl ester of GSH (IP-GSH), which was shown to replenish NP-SH concentrations in all tissues except the liver of animals previously administered phorone. When animals were pre-treated with phorone plus BSO and then exposed to 100 ppm MeI for 2 h, there was a potentiation of the toxicity of MeI as judged by the clinical observations on the animals. In contrast, treatment with IP-GSH prior to and during exposure to MeI for 4 h afforded a marked protection to the olfactory epithelium. In order to inhibit cytochromes P450, animals were pre-treated with cobalt protoporphyrin IX. This decreased hepatic cytochrome P450 concentrations by > 90%, but when animals were then exposed to 100 ppm MeI for 4 h there was no effect on the severity of the olfactory lesion. These results indicate that conjugation of MeI with GSH is a detoxification rather than an activation pathway. Also, there is no major role for cytochrome P450-dependent oxidation in the development of the olfactory lesion.
School of Biomolecular Sciences, Liverpool John Moores University, UK.
M P
MP
Chamberlain
E A
EA
Lock
B A
BA
Gaskell
C J
CJ
Reed
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004357:Drug Synergism; D004848:Epithelium / Q000187:drug effects / Q000201:enzymology; D005982:Glutathione Transferase / Q000378:metabolism*; D006847:Hydrocarbons, Iodinated / Q000009:adverse effects*; D007659:Ketones / Q000494:pharmacology; D008297:Male; D009296:Nasal Cavity / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012137:Respiratory System / Q000187:drug effects / Q000201:enzymology; D012903:Smell / Q000187:drug effects*
D006847:Hydrocarbons, Iodinated; D007659:Ketones; C018637:phorone; D003577:Cytochrome P-450 Enzyme System; C014055:methyl iodide; D005982:Glutathione Transferase