PB-PK derived metabolic constants, hepatotoxicity, and lethality of BrCCl3 in rats pretreated with chlordecone, phenobarbital, or mirex

Abstract Pharmacokinetic modeling has been very useful in examining the complex relationships between exposure concentration and target tissue dose. This study utilizes a physiologically based pharmacokinetic (PB-PK) modeling approach for assessing the metabolism of BrCCl 3 and to investigate its relationship with hepatotoxicity and lethality. Male Sprague-Dawley rats maintained for 15 days on normal diet (control), or on diets containing either chlordecone (CD, 10 ppm), phenobarbital (PB, 225 ppm) or mirex (M, 10 ppm), were used in gas uptake studies to determine the kinetic constants of BrCCl 3 metabolism. Four initial concentrations of BrCCl 3 at approximately 30, 200, 700, and 3000 ppm were used for each group. The uptake data were analyzed by computer simulation using a PB-PK model containing relevant tissue solubilities and physiological parameters as well as an equation describing the behavior of BrCCl 3 in the closed chamber atmosphere. Liver injury was assessed by serum enzyme elevations (alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase) and histopathological examination, at 24 hr after the exposure to BrCCl 3 . Another group of similarly pretreated rats was exposed to BrCCl 3 and observed over a 14-day period for mortality. Dietary exposures resulted in increased V maxc value for BrCCl 3 metabolism as compared to control (3.55 ± 0.14 mg/hr/kg) for PB (8.52 ± 0.28 mg/hr/kg) and M (5.06 ± 0.19 mg/hr/kg) but not for CD (3.92 ± 0.19 mg/hr/kg). K fc , the first-order rate constant for BrCCl 3 metabolism, was decreased after PB (12.9 ± 0.5 hr −1 /kg) and increased after M (17.6 ± 0.5 hr −1 /kg), but unchanged after CD (15.5 ± 0.6 hr −1 /kg) exposure as compared to control (15.0 ± 0.3 hr −1 /kg). The total amount of BrCCl 3 metabolism at any initial concentration employed remained unchanged in all the pretreated groups as compared to control. However, the amount of BrCCl 3 metabolized through saturable pathway only, at higher initial concentrations, was increased in the PB and M pretreated groups, but not in the CD pretreated group. It is concluded that the rates of metabolism of BrCCl 3 were unchanged after CD pretreatment as compared to control, while PB and M pretreatments alter both the saturable and first-order rates. Serum enzymes were significantly increased in all the groups after exposure to BrCCl 3 at 200 and 700 ppm concentrations. The increase was more pronounced in PB and M pretreated groups as compared to control and CD pretreated groups. Similarly, histopathological examination of liver showed alterations in the lobular architecture, the extent of alterations being dependent on the dose of BrCCl 3 and the pretreatment. The changes were characterized by the presence of swollen (vacuolated) cells and centrilobular necrosis. The alterations were more severe in PB and M pretreated groups compared to control and CD treated groups. However, differences in BrCCl 3 lethality were evident at 200 ppm, the order of lethality being CD > PB, while M and control rats were not affected. The present study suggests that CD pretreatment results in significant amplification of hepatotoxic and lethal effects of BrCCl 3 despite a lack of significant increase in the metabolism of BrCCl 3 , while PB and M pretreatments potentiated these hepatotoxic effects by increasing the metabolism of BrCCl 3 . These findings were associated with only a marginal increase in lethality in the case of PB and no increase in lethality in the case of M treatment. In conclusion, while enhanced bioactivation of BrCCl 3 may lead to increased infliction of liver injury, progression of that injury leading to animal lethality is not associated with the increased metabolic bioactivation.