Strain-dependent responses to mineral hydrocarbons in female Fischer-344 and Sprague-Dawley rats

摘要

Mineral hydrocarbons (MHC) produce hepatic microgranulomas and granulomas following repeated administration to female Fischer-344 (F-344) rats. Female Sprague-Dawley (S-D) rats are less sensitive to these MHC-induced hepatic effects. Comparative studies were conducted to characterize the pharmacokinetics and disposition of a representative C26 MHC, [1-14C]1-eicosanylcyclohexane ([14C]EICO), in these two rat strains. Following a single oral dose of MHC, F-344 rats had a higher blood Cmax of [14C]EICO, a longer time to Cmax, and a greater blood AUC compared to S-D rats. Fecal excretion was the major route of elimination of parent [ 14C]EICO for both rat strains. Both rat strains eliminated 11% of the dose in the urine by 96 h. However, S-D rats eliminated the majority of [14C]EICO-metabolites in the urine by 16 h, while F-344 rats excreted [14C] equivalents in a time-dependent manner. At 96 h, 3% of the radioactive dose was recovered in livers of F-344 rats, but only 0.1% in S-D rats. Parent [14C]EICO was determined to be retained in livers of F-344 rats. Only metabolites of [14C]EICO were present in urine, the two major being 12-cyclohexyldodecanoic acid and 10-cyclohexyldecanoic acid. Inhibition of hepatic P450 activity using ABT prior to MHC administration resulted in a significant increase in [14C]EICO retention in livers of F-344 rats at 96 h. Pretreatment with clofibrate, a CYP4A inducer, decreased the amount of [14C]EICO retained in livers of F-344 rats at 96 h. Dietary exposure from MHC for 2 weeks resulted in an increased amount of MHC retained in livers of F-344 rats, whereas little was retained in treated S-D rats. The majority of MHC was retained in hepatocytes, whereas little was detected in Kupffer cells (KC). This was evidenced following transmission electron microscopy analysis of liver sections of F-344 rats. Multiple MHC droplets were observed in hepatocytes, while few droplets were detected in KC. Results from these studies suggest that inherent strain-differences in systemic exposure, rates of elimination, and hepatic retention of MHC exist following MHC exposure. The CYP4 enzyme family plays a role in the metabolism, clearance, and retention of [14C]EICO, while the phagocytic activity of KC is less significant after a single oral dose of MHC. In addition, repeated exposure of MHC alters the morphology of hepatocytes of F-344 rats but not S-D rats. These differences just described suggest that F-344 rats are inherently predisposed to the observed MHC-induced hepatic effects. (Abstract shortened by UMI.)