Investigations of the pathways of toxicity of methyl iodide in the rat nasal cavity.
The monohalomethane methyl iodide (MeI) is a site specific toxin within the nasal cavity of the rat, selectively damaging the olfactory epithelium (OE) whilst respiratory epithelium (RE) is spared. The aim of this study was to investigate the rates and routes of metabolism of MeI within the nasal cavity, in order to understand the reasons for the observed site-selectivity. Cytosolic glutathione S-transferases (GSTs) of both OE and RE catalysed the conjugation of MeI with glutathione (GSH), but rates were 4-fold higher in OE than RE. The product of this reaction was confirmed as S-methyl GSH. In both OE and liver the GST catalysing the conjugation of MeI was shown to belong to the theta class. No cytochrome P450-dependent oxidation of MeI to formaldehyde could be detected in incubations containing hepatic or olfactory microsomes. Intact nasal turbinates were incubated with [14C]-MeI, and a dose- and time-dependent covalent binding of MeI to olfactory protein was demonstrated. The rates of protein methylation were found to be similar in OE and RE. Thus the only parameter that correlates with the site-selectivity of the observed lesion is the rate of conjugation of MeI with GSH. Whether toxicity is due to production of a reactive metabolite or GSH depletion per se, remains to be elucidated.
School of Biomolecular Sciences, Liverpool John Moores University, UK.
M P
MP
Chamberlain
E A
EA
Lock
C J
CJ
Reed
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D005557:Formaldehyde / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000502:physiology; D006847:Hydrocarbons, Iodinated / Q000378:metabolism / Q000633:toxicity*; D008297:Male; D008745:Methylation; D009296:Nasal Cavity / Q000187:drug effects*; D010084:Oxidation-Reduction; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar
D006847:Hydrocarbons, Iodinated; D005557:Formaldehyde; D003577:Cytochrome P-450 Enzyme System; C014055:methyl iodide; D005982:Glutathione Transferase; D005978:Glutathione