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Mechanisms of interleukin-2-induced depression of hepatic cytochrome P-450 in mice
Abstract:
Interleukin-2 (15 micrograms/mouse, i.p. twice daily for 4 days and once on the 5th day) significantly lowered cytochrome P-450 and heme content and increased heme oxygenase mRNA accumulation; the activities of 7-ethoxycoumarin O-deethylase, ethoxy- and pentoxyphenoxazone O-dealkylases were decreased. The activity of the type O form of hepatic xanthine oxidase increased, but there was no increase in lipid peroxide, expressed in terms of microsomal malondialdehyde. In vivo inactivation of xanthine oxidase activity by feeding mice with tungstate did not substantially change the degree of interleukin-2-induced cytochrome P-450 depression, suggesting that the two processes are not causally linked. Induction of tolerance to endotoxin by a 4-day pretreatment with lipopolysaccharide resulted in 50% protection against this depression despite inhibition of the interleukin-2 induced formation of tumor necrosis factor. This suggests that the release of tumor necrosis factor per se does not fully account for the depression of cytochrome P-450. Dexamethasone, already used in patients to reduce the toxicity of interleukin-2 therapy, provided full protection against the cytochrome P-450 depression.
Insights
Interleukin-2 (IL-2) therapy can decrease cytochrome P-450 levels in mice. Dexamethasone fully protected against this effect, suggesting its potential to mitigate IL-2 toxicity.
Area of Science:
- Pharmacology
- Biochemistry
- Toxicology
Background:
- Interleukin-2 (IL-2) is a cytokine used in cancer therapy.
- IL-2 therapy can cause adverse effects, including potential liver toxicity.
- Cytochrome P-450 enzymes are crucial for drug metabolism and detoxification.
Purpose of the Study:
- To investigate the effects of Interleukin-2 (IL-2) on cytochrome P-450 and related enzymes.
- To explore the mechanisms underlying IL-2-induced changes in drug-metabolizing enzymes.
- To evaluate the protective effects of dexamethasone against IL-2-induced toxicity.
Main Methods:
- Mice were treated with Interleukin-2 (IL-2) at specific dosages and schedules.
- Enzyme activities (cytochrome P-450, O-deethylases, O-dealkylases, xanthine oxidase) and heme content were measured.
- Heme oxygenase mRNA levels and lipid peroxide content were assessed.
- In vivo inactivation of xanthine oxidase and endotoxin tolerance were induced.
- Mice were pretreated with dexamethasone or lipopolysaccharide.
Main Results:
- IL-2 significantly decreased cytochrome P-450 and heme content, and reduced the activity of several drug-metabolizing enzymes.
- IL-2 increased heme oxygenase mRNA and hepatic xanthine oxidase activity, but not lipid peroxide levels.
- Inactivating xanthine oxidase did not prevent IL-2-induced cytochrome P-450 depression.
- Endotoxin tolerance offered partial protection against IL-2 effects, and tumor necrosis factor did not fully mediate the depression.
- Dexamethasone completely prevented the IL-2-induced decrease in cytochrome P-450.
Conclusions:
- Interleukin-2 (IL-2) administration negatively impacts hepatic drug-metabolizing enzymes, including cytochrome P-450.
- The mechanisms involve heme metabolism and xanthine oxidase, but not solely tumor necrosis factor.
- Dexamethasone effectively protects against IL-2-induced cytochrome P-450 depression, highlighting its therapeutic potential in managing IL-2 toxicity.