Effect of a Single Administration of Benzene, Toluene orm-Xylene on Carboxyhaemoglobin Elevation and Metabolism of Dichloromethane in Rats

Abstract

The effect of a single administration of aromatic hydrocarbons (AHCs) on the metabolic activity responsible for the biotransformation of dichloromethane (DCM) to carbon monoxide (CO) was investigated using adult female rats. In rats treated orally with benzene (1.5 ml kg−1), toluene (2.0 ml kg−1) or m‐xylene (2.0 ml kg−1) 16–24 h prior to DCM (3 mmol kg−1, i.p.), the carboxyhaemoglobin (COHb) level was elevated, reaching peaks in blood at 21%, 16% and 23%, respectively, compared to the peak of ca. 10% in rats treated with DCM only. Their effects on COHb generation were highly dependent on the time interval between each AHC and DCM treatment, since an early administration of m‐xylene or toluene decreased the COHb elevation. The half‐life of DCM in blood was shortened significantly, indicating that the metabolic degradation of DCM was enhanced by the AHCs. Disulfiram (3.4 mmol kg−1, p.o.) blocked COHb elevation completely, suggesting that the metabolic conversion of DCM to CO is mediated by cytochrome P‐450 2E1 (P4502E1). Corresponding increases in the concentration and half‐life of DCM in blood were also observed. A single administration of the AHCs did not alter the hepatic glutathione level, suggesting that the increase in DCM‐induced COHb elevation was not due to hepatic glutathione depletion. In vitro studies showed that the hepatic microsomal metabolism of nitrosodimethylamine and p‐nitrophenol was significantly increased by a single dose of each AHC. Total cytochrome P‐450 content and p‐nitroanisole demethylase activity were also increased; however, only toluene and m‐xylene were effective inducers for aminopyrine N‐demethylase. Therefore, benzene appears to be a selective inducer for P4502E1 compared to other alkylbenzenes. The results indicate that even a single dose of benzene, toluene or m‐xylene may induce the activity of P4502E1 significantly, which is responsible for the increased generation of COHb from DCM, as demonstrated in the present study.

Methylene chloride protects against cecal ligation and puncture-induced acute lung injury by modulating inflammatory mediators

“…The rats were divided into five groups (n = 10) and intragastrically administered with the different treatments 2 h before CLP: (1) SHAM group, SD rats intragastrically administered 0.4 ml olive oil and underwent laparotomy without CLP operation; (2) CLP group, rats intragastrically administered 0.4 ml olive oil and underwent CLP operation; (3) MC group, rats were intragastrically administered with MC(100 mg/kg) in 0.4 ml of olive oil 2 h before CLP induction [12]; (4) MC+ DSF group, disulfiram (DSF), a metabolic inhibitor of MC, were intragastrically administered (1 g/kg) in 0.4 ml of olive oil 12 hours before CLP [13]; and then intragastrically administered 0.4 ml 100 mg/kg MC dissolved in olive oil 2 h before CLP; and (5) DSF group, DSF were intragastrically administered (1 g/kg) in 0.4 ml of olive oil 12 h before CLP.…”

“…Disulfiram (DSF, Sigma Chemical Co.) was diluted also in olive oil at a concentration of 250 mg/ml and given orally by gavage, at a dose of 1000 mg/kg [13]. Olive oil was purchased from Beijing Huayuan Life Technology & Trade Development Co. (China).…”

Effects of betaine supplementation on hepatic metabolism of sulfur-containing amino acids in mice

“…Hepatic microsomal drug metabolizing enzyme activities were determined using the methods described elsewhere [24]. The concentration of cytochrome P-450 was estimated from the CO difference spectrum.…”

Alteration in Metabolism and Toxicity of Acetaminophen Upon Repeated Administration in Rats

“…On the other hand, its potential adverse effects at a lower or therapeutic dose have hardly been explored. Recently we observed that APAP, at a dose incapable of inducing hepatic injury, enhanced the metabolic conversion of dichloromethane to carbon monoxide (2), a reaction mediated mostly by CYP2E1 (3,4). This implies that a low dose of APAP may paradoxically increase the biotransformation and toxicity of a xenobiotic that is metabolically converted to a toxic metabolite by the same CYP enzymes.…”