Inhibition of rat lung mixed-function oxidase activity following repeated low-level toluene inhalation: possible role of toluene metabolites.

Toluene is a commonly used solvent that has been shown to alter mixed-function oxidase (MFO) activity, in an organ- and isozyme-specific pattern, following intraperitoneal administration. The purpose of this study was to determine whether similar changes occurred following repeated, low-level inhalation exposure, and to investigate the role of toluene metabolites in these alterations. Exposure to 375 ppm toluene, 6 h/d for up to 5 d, resulted in significant inhibition of the activity of pulmonary arylhydrocarbon hydroxylase (AHH), cytochrome P-4502B1 (CYP2B1), and CYP4B1, but not CYP1A1. After exposure to lower toluene levels (125 ppm, 6 h/d, 3 d), the activities of lung AHH, CYP2B1, and CYP4B1 were also significantly decreased, but in a dose-related manner. MFO activity was not consistently altered in liver. Control pulmonary or liver microsomes were incubated with various concentrations (0.01-10 mM) of toluene or its metabolites and CYP2B1, CYP1A1, and/or CYP4B1 activities were subsequently determined. Benzaldehyde produced a significant dose-related inhibition in the activity of all three lung P-450s examined (IC50 10(-3) M). Toluene was found to be a more potent inhibitor of lung CYP2B1 and CYP1A1 (IC50, 10(-4) M) than benzaldehyde, but neither toluene nor benzyl alcohol was an effective inhibitor of lung CYP4B1. Toluene and its metabolites were weaker inhibitors of CYP1A1 than of CYP2B1. For CYP2B1 and CYP1A1, the order of inhibitory potency was toluene > benzaldehyde > benzyl alcohol and suggests that both the parent molecule and its metabolites may act in concert to inhibit catalytic activity of these cytochromes. The MFO inhibition seen after repeated low-level toluene inhalation exposure could result in altered metabolic profiles of other xenobiotics in an organ-specific fashion.

Local treatment of prosthetic vascular graft infection with multivesicular liposome-encapsulated amikacin.

BACKGROUND: Contaminated surgical fields limit the use of prosthetic vascular grafts. We studied the efficacy of sustained-release amikacin applied locally to contaminated grafts in the prevention of infectious complications. MATERIALS AND METHODS: Thirty-one New Zealand white rabbits underwent placement of a polytetrafluoroethylene (PTFE) interposition graft in a 1-cm segment of the descending aorta. The surgical field was infected with application of 10(5) to 10(8) Staphylococcus aureus organisms suspended in normal saline solution. Nineteen rabbits underwent contaminated aortic graft placement without treatment. Twelve rabbits were treated with local application of 2.5 ml of amikacin encapsulated in lipid particle-based sustained-release dosage form. Rabbits were observed for 2 weeks and then evaluated for the presence of graft infection. RESULTS: Seventy-five percent of the treated rabbits survived without evidence of graft infection or systemic sepsis versus 37% in the untreated group (P < 0.04). Cultures verified the absence of organisms in all surviving rabbits without clinical infection. CONCLUSIONS: Sustained-release lipid particle-encapsulated amikacin applied to contaminated PTFE grafts increased survival and decreased postoperative graft infections. Adjunctive use of local, delayed-release antibiotics in contaminated vascular beds may allow wider clinical use of prosthetic grafts.

Phenytoin treatment and folate supplementation affect folate concentrations and methylation capacity in rats.

Phenytoin (PHT) has long been known to cause folate depletion with chronic use. In animal models PHT has been shown to interfere with folate-dependent one-carbon metabolism. Folic acid supplementation in humans has been shown to restore blood levels of folates to normal, but the effects of folic acid supplementation on the PHT-induced effects on one-carbon metabolism have not been addressed. In the present study rats were treated for 8 wk with 1) PHT, 2) folic acid, 3) PHT plus folic acid or 4) vehicle (propylene glycol). Phenytoin treatment caused a decrease in weight gain over the 8 wk of treatment. This effect on weight gain was reversed by folic acid supplementation, but the decrease in brain folate concentration caused by PHT was not reversed by folic acid supplementation, which by itself apparently caused a decrease in brain folate concentration. Phenytoin treatment tended to increase methylation capacity (S-adenosylmethionine:S-adenosylhomocysteine ratio) in the brain and decrease methylation capacity in the liver. Folate supplementation by itself increased methylation capacity in the liver but had no effect in the brain. Folic acid and PHT apparently had independent but opposite effects in the liver, leading to a normalization of methylation capacity. These data suggest that folic acid supplementation in PHT therapy may be effective in reversing the peripheral effects of chronic PHT treatment on one-carbon metabolism but not the central effects.

The effect of toluene on rat lung benzo[a]pyrene metabolism and microsomal membrane lipids.

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.