Maturational development of drug-metabolizing enzymes in dogs

J. C. Kawalek From the Veterinary Pharmacology/Toxicology Branch, Division of Veterinary Medical Research, Center for Veterinary Medicine, Food and Drug Administration, Agricultural Research Center — East, Building 328A, Beltsville, MD 20705.

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K. R. El Said From the Veterinary Pharmacology/Toxicology Branch, Division of Veterinary Medical Research, Center for Veterinary Medicine, Food and Drug Administration, Agricultural Research Center — East, Building 328A, Beltsville, MD 20705.

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SUMMARY

A qualitative and quantitative assessment was made of the development of hepatic drug-metabolizing enzymes (dme) in dogs as part of a study of the ability of animal test species to metabolize drugs. The following dme variables were measured in this study: amount of cytochromes P-450 and b5 activity of the nadph and nadh- dependent reductases associated with each of these cytochromes; activity of cytochrome P-450-mediated enzymes, including aniline and coumarin hydroxylases, aminopyrine N-demethylase, and 7-ethoxycoumarin O-deethylase; activity of a uridine diphosphoglucuronic acid glucuronyl transferase with 4-methylumbelliferone as substrate; and glutathione-S-transferase activities, with dinitrochlorobenzene and dichloronitrobenzene as substrates. Most enzyme components had achieved maximal amount or activity by the fifth to eighth week after birth; they tended to decrease after weaning, although the activity of dichloronitrobenzene-glutathione transferase in geriatric dogs (312 to 525 weeks old) was approximately twofold greater than that of 8-week-old pups. There were no gender-related differences in any of the enzyme amounts or activities determined. Individual variation was pronounced even in the homogeneous colony from which these dogs were obtained.

SUMMARY

A qualitative and quantitative assessment was made of the development of hepatic drug-metabolizing enzymes (dme) in dogs as part of a study of the ability of animal test species to metabolize drugs. The following dme variables were measured in this study: amount of cytochromes P-450 and b5 activity of the nadph and nadh- dependent reductases associated with each of these cytochromes; activity of cytochrome P-450-mediated enzymes, including aniline and coumarin hydroxylases, aminopyrine N-demethylase, and 7-ethoxycoumarin O-deethylase; activity of a uridine diphosphoglucuronic acid glucuronyl transferase with 4-methylumbelliferone as substrate; and glutathione-S-transferase activities, with dinitrochlorobenzene and dichloronitrobenzene as substrates. Most enzyme components had achieved maximal amount or activity by the fifth to eighth week after birth; they tended to decrease after weaning, although the activity of dichloronitrobenzene-glutathione transferase in geriatric dogs (312 to 525 weeks old) was approximately twofold greater than that of 8-week-old pups. There were no gender-related differences in any of the enzyme amounts or activities determined. Individual variation was pronounced even in the homogeneous colony from which these dogs were obtained.

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