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Endotoxin depression of hepatic mixed function oxidase system in C3H/HeJ and C3H/HeN mice
Abstract:
The effect of endotoxin to depress the hepatic drug-metabolizing enzyme activity has been studied in the C3H/HeJ and C3H/HeN strains of mice. The C3H/HeJ mouse strain is generally considered to be unresponsive to the biological effects of endotoxin. However, injection of these mice with 0.5 mg/kg body weight of E.coli endotoxin (Westphal extracted) produced a decrease in the rate of N-demethylation of ethylmorphine and in the levels of cytochrome P-450 and cytochrome b5 comparable to that observed in the endotoxin-sensitive C3H/HeJ mouse strain. Although the mechanism of endotoxin action to decrease hepatic microsomal drug-metabolizing activity is presently unknown, the results suggest that: 1) the C3H/HeJ mouse stain is responsive to this endotoxin effect, and 2)that cellular constituents other than B-cells or macrophages are probably involved in eliciting the response, since these cells of the C3H/HeJ mouse are unresponsive to endotoxin.
Insights
Endotoxin exposure decreased hepatic drug-metabolizing enzyme activity in both endotoxin-unresponsive and responsive mouse strains. This suggests endotoxin
Area of Science:
- Pharmacology
- Toxicology
- Immunology
Background:
- Endotoxin (lipopolysaccharide) is a component of Gram-negative bacteria.
- Hepatic drug-metabolizing enzymes are crucial for xenobiotic clearance.
- The C3H/HeJ mouse strain is typically considered endotoxin-unresponsive.
Purpose of the Study:
- To investigate the effect of endotoxin on hepatic drug-metabolizing enzyme activity.
- To compare the response in endotoxin-sensitive (C3H/HeN) and endotoxin-unresponsive (C3H/HeJ) mouse strains.
Main Methods:
- Administration of E. coli endotoxin (Westphal extracted) to C3H/HeJ and C3H/HeN mice.
- Measurement of N-demethylation rate of ethylmorphine.
- Quantification of cytochrome P-450 and cytochrome b5 levels.
Main Results:
- Endotoxin administration decreased ethylmorphine N-demethylation in both C3H/HeJ and C3H/HeN mice.
- Cytochrome P-450 and cytochrome b5 levels were reduced by endotoxin in both strains.
- The observed decrease in enzyme activity was comparable between the two mouse strains.
Conclusions:
- The C3H/HeJ mouse strain exhibits responsiveness to the enzyme-depressing effects of endotoxin.
- Cellular components other than B-cells or macrophages are likely involved in mediating endotoxin's effect on hepatic enzymes.