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Effects of methapyrilene on DNA synthesis in mice and rats following continuous dietary exposure
F C Richardson1, D M Copple, P I Eacho
1Toxicology Research Laboratories, Eli Lilly and Co., Greenfield, IN 46140.
Abstract:
The effects of the antihistamine methapyrilene (MP) on DNA synthesis in rats and mice were investigated. Previous studies have demonstrated a dose response for tumor induction in the rat but no carcinogenic effect in the mouse. To study the role of DNA synthesis in MP carcinogenesis, rats and mice were administered MP at doses of 0, 62.5, 125, 250 or 1000 p.p.m. in the diet for a period of 1-12 weeks. Bromodeoxyuridine was administered continuously using an osmotic minipump during the last week of treatment to provide an index of DNA synthesis. Results demonstrated that in the rat 250 and 1000 p.p.m. MP increased DNA synthesis in a dose-dependent manner that correlated with the tumor response in previous oncogenic studies. MP at 62.5 p.p.m. did not increase DNA synthesis, indicating a no effect level for cell proliferation and suggesting a no effect level for carcinogenicity by this compound in the rat. MP did not induce DNA synthesis in mice after exposure to 1000 p.p.m. for 12 weeks, nor did it induce changes in serum chemistries or liver histopathology suggestive of overt toxicity as was seen in the rat at 1000 p.p.m. The correlations between labeling index and tumorigenicity in the rat and mouse strongly support a role of cell proliferation in the carcinogenic mechanism of MP.
Insights
The antihistamine methapyrilene (MP) increased DNA synthesis in rats, correlating with tumor formation. MP did not affect DNA synthesis in mice, suggesting cell proliferation plays a role in MP carcinogenesis.
Area of Science:
- Toxicology
- Carcinogenesis
- Molecular Biology
Background:
- Antihistamine methapyrilene (MP) shows a dose-response for tumor induction in rats but not mice.
- Understanding the role of DNA synthesis in MP carcinogenesis is crucial.
Purpose of the Study:
- To investigate the effects of methapyrilene (MP) on DNA synthesis in rats and mice.
- To correlate DNA synthesis changes with MP's known carcinogenic effects.
Main Methods:
- Rats and mice were fed MP at varying doses (0-1000 p.p.m.) for 1-12 weeks.
- Bromodeoxyuridine was administered via osmotic minipump to measure DNA synthesis during the final week.
Main Results:
- In rats, MP at 250 and 1000 p.p.m. dose-dependently increased DNA synthesis, aligning with prior tumor data.
- A dose of 62.5 p.p.m. MP did not elevate DNA synthesis in rats, indicating a potential no-effect level.
- MP did not induce DNA synthesis or overt toxicity in mice, even at 1000 p.p.m.
Conclusions:
- Increased DNA synthesis in rats correlates with methapyrilene's carcinogenicity.
- The lack of DNA synthesis induction in mice suggests cell proliferation is a key mechanism in MP-induced carcinogenesis.