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.)
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/280034 |
| Date | January 2002 |
| Creators | Halladay, Jason |
| Contributors | Sipes, I. Glenn |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | en_US |
| Detected Language | English |
| Type | text, Dissertation-Reproduction (electronic) |
| Rights | Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. |
Page generated in 0.0016 seconds