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The effect of toluene on rat lung benzo[a]pyrene metabolism and microsomal membrane lipids
G M Furman1, D M Silverman, R A Schatz
1Toxicology Program, Northeastern University, Boston, MA 02115.
Abstract:
Toluene (1 g/kg, i.p., 1 and 4 h) was shown to decrease total cytochrome P-450 (P450) content in rat lung. At both timepoints, reduction in pulmonary P450 content was associated with a decrease in aryl hydrocarbon hydroxylase (AHH) activity, a detoxication pathway for benzo[a]pyrene (BaP). At 4 h, toluene increased the toxication/detoxication ratios of BaP metabolites in pulmonary microsomes, primarily via inhibition of hydroxy metabolite formation. The structurally analogous solvents p- and m-xylene have been previously shown to produce a similar pattern of MFO changes in rat lung; the inhibition of BaP metabolism was found to be related to alterations in pulmonary microsomal lipids following administration of p- but not m-xylene. In the present study, toluene-induced alterations in MFO parameters were not found to be associated with changes in microsomal lipids. Toluene did not affect either total phospholipid or cholesterol content at either timepoint. Similarly, no changes in speciated phospholipids were observed. Membrane integrity, expressed as conjugated diene formation, also remained unchanged following toluene administration. Toluene did, however, decrease microsomal inner-core membrane fluidity at 4 h but had no effect on membrane leaflet fluidity at either timepoint. These data suggest that the fatty acid composition of microsomal lipids may play a role in the metabolic alterations observed in pulmonary microsomes following toluene administration.
Insights
Toluene exposure reduced lung cytochrome P-450 (P450) and aryl hydrocarbon hydroxylase (AHH) activity, impairing benzo[a]pyrene detoxification. Unlike related solvents, toluene did not alter lung microsomal lipids but affected membrane fluidity.
Area of Science:
- Toxicology and Environmental Health
- Biochemistry and Molecular Biology
- Pharmacology
Background:
- Solvents like p- and m-xylene affect mixed-function oxidase (MFO) enzymes in rat lungs, altering benzo[a]pyrene (BaP) metabolism.
- These xylene-induced changes were linked to alterations in pulmonary microsomal lipids.
- The impact of toluene, a structurally similar solvent, on lung MFO and microsomal properties requires investigation.
Purpose of the Study:
- To investigate the effects of toluene on cytochrome P-450 (P450) content and aryl hydrocarbon hydroxylase (AHH) activity in rat lungs.
- To determine if toluene alters BaP metabolism ratios and to examine its effects on pulmonary microsomal lipid composition and membrane fluidity.
- To compare toluene's effects with those of p- and m-xylene on lung MFO parameters.
Main Methods:
- Rats were administered toluene (1 g/kg, i.p.) and evaluated at 1 and 4 hours.
- Pulmonary P450 content and AHH activity were measured.
- BaP toxication/detoxication ratios were assessed, alongside measurements of total phospholipids, cholesterol, speciated phospholipids, membrane integrity (conjugated dienes), and membrane fluidity (inner-core and leaflet).
Main Results:
- Toluene decreased total P450 content and AHH activity in rat lungs at both timepoints.
- At 4 hours, toluene increased BaP toxication/detoxication ratios by inhibiting hydroxy metabolite formation.
- Toluene did not alter total or speciated phospholipids, cholesterol content, or membrane integrity, but it decreased inner-core membrane fluidity at 4 hours.
Conclusions:
- Toluene impairs lung BaP detoxification by reducing P450 and AHH activity and altering metabolite formation.
- Unlike p-xylene, toluene's effects on MFO parameters are not associated with changes in overall microsomal lipid content or integrity.
- The observed decrease in inner-core membrane fluidity suggests that alterations in fatty acid composition may contribute to toluene-induced metabolic changes in pulmonary microsomes.