Diet-induced alterations in theobromine disposition and toxicity in the rat

doi:10.1016/0041-008X(86)90265-6

Toxicology and Applied Pharmacology

Volume 84, Issue 3, July 1986, Pages 593-598

https://doi.org/10.1016/0041-008X(86)90265-6 Get rights and content

Abstract

To assess the potential influence of diet on theobromine (TBR) disposition and the development of TBR-induced thymic and testicular toxicity, male Sprague-Dawley rats were given the following diets ad libitum for 28 days: (1) semipurified (S); (2) commercial chow (Ch); (3) semipurified + 0.6% TBR (S + TBR); or (4) commercial chow + 0.6% TBR (Ch + TBR). Toxicity endpoints determined in each TBR group indicated that Ch + TBR-treated animals did not exhibit the marked reduction in body weight or testicular atrophy induced by the S + TBR diet, although thymic weight was lower regardless of diet. Metabolic studies performed after the 28-day feeding period using 5 mg/kg TBR + 10 μCi [8-¹⁴C]TBR revealed an overall inductive effect of Ch on TBR metabolism as shown by increased urinary excretion (0–24 hr) of the major TBR metabolite, 6-amino-5[N-methylformylamino]-1-methyluracil (6-AMMU), as well as 7-methylxanthine + 3-methylxanthine (7-MX + 3-MX) and 3,7-dimethyluric acid (3,7-DMU). Consumption of 0.6% TBR for 28 days in either S or Ch diets also induced its own metabolism, as shown by decreased urinary excretion of unchanged TBR and increased conversion primarily to 3,7-DMU. Fecal ¹⁴C elimination (0–24 hr) was similar between animals fed S and Ch diets, indicating no effect of control diet on TBR bioavailability. Since serum TBR concentrations and overall toxicity were lower in Ch + TBR-treated animals than in S + TBR treated animals, yet TBR bioavailability was similar, this effect was attributed to the inducing potential of the Ch diet on TBR metabolism and clearance. Investigators are cautioned to consider the potential effect of diet on metabolism when performing and evaluating toxicological studies.

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^☆: Presented at the 24th Annual Meeting of the Society of Toxicology, March 19, 1985, San Diego, Calif; submitted by CAS in partial fulfillment of the requirements for the degree of Doctor of Philosophy, Department of Pharmacology, The Pennsylvania State University, Hershey, Pa.

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Diet-induced alterations in theobromine disposition and toxicity in the rat☆

Abstract

Toxicology

Amer. J. Clin. Nutr.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Food Cosmet. Toxicol.

Caffeine metabolism in the newborn

Clin. Pharmacol. Ther.

Metabolic pathway of theobromine in the rat and identification of two new metabolites in human urine

J. Agric. Food Chem.