Pharmacogenetics is the study of genetic differences which
affect the therapeutic efficacy and toxicity of drugs and the response
to chemicals to which animals or people are exposed intentionally or otherwise.
The genetic differences may be within species (mutations or defects) or
between species (differences in structure of specific proteins). Genetic
variation in drug metabolism is the most common source of pharmacogenetic
differences. In many cases, pharmacogenetic variation is not apparent until
the animal or person is exposed to a drug or chemical, but the outcome
may then be fatal. Syndromes associated with pharmacogenetic variants are
usually observed first clinically. Without identifying the underlying molecular
mechanism, this information is only of limited use to guide drug development
safety assessment, and drug selection and use in veterinary and human medicine.
With the support of the Max Bell Foundation, we have established a Laboratory
of Comparative Pharmacogenetics at the Atlantic Veterinary College,
University of Prince Edward Island dedicated to understanding the molecular
basis of pharmacogenetic variation within and between species with the
goals of improving the safety of drugs in human and veterinary medicine,
avoiding drug- and chemical-induced toxicity, and increasing the exchange
of information between human and veterinary pharmacogenetics.
This program is integrated with our molecular toxicology program, but emphasizes the pharmacogenetic aspects of the research questions. Individual projects in the current research program include:
1. Comparative pharmacogenetics of sulfonamide hypersensitivity reactions.
2. Phenobarbital-induced hepatotoxicity and thyroid hormone suppression.
3. Mechanism of carprofen hepatitis in dogs, a model of NSAID hepatopathy.
4. In vitro prediction of metabolic drug-drug interactions.
5. Genetic factors in susceptibility to breast cancer on P.E.I.- see our cancer research program for details.
Examples of recent publications include:
Cribb AE, Spielberg SP, and Griffin GE. N4-hydroxylation of sulfamethoxazole by cytochrome P450 of the CYP2C subfamily and microsomal reduction of its hydroxylamine metabolite in human and rat hepatic microsomes. Drug Metab Dispos 23: 406-414, 1995.
Cribb AE, Belle L, Trepanier L, Spielberg SP. Adverse reactions to sulphonamide and sulphonamide-trimethoprim combination products: clinical syndromes and pathogenesis. Adverse Drug Reactions and Toxicological Reviews, 15: 9-50, 1996
Nuss CE, Grant DM, Spielberg SP, Cribb AE. Further investigations of the role of acetylation in sulfonamide hypersensitivity reactions. Biomarkers, 1: 267-272, 1996.
Trepanier LA, Kunal R, Winand NJ, Spielberg SP, and Cribb AE. Cytosolic arylamine N-acetyltransferase deficiency in the dog and other canids is due to an absence of NAT genes. Biochemical Pharmacology, 54: 73-80, 1997.
Trepanier LA, Cribb AE, Spielberg SP, and Ray K. Deficiency of cytosolic arylamine N-acetylation in the domestic cat and wild felids due to the presence of only a single NAT1-like gene. Pharmacogenetics, 8: 169-179, 1998.
McCrea J, Cribb AE, Rushmore T, Osborne B, Gillin L, Lo M-W, Waldman S, Bjornsson T, Spielberg S, Goldberg MR. Phenotypic and Genotypic Investigations of a Healthy Volunteer Deficient in the Conversion of Losartan to its Active Metabolite, E-3174. Clin Pharmacol Ther, 64: 348-52, 1999.
Cribb AE, McQuaid T, Renton KW. Effect of LPS-evoked inflammation on hepatic microsomal formation and reduction of sulfamethoxazole hydroxylamine in the rat. Biochem Pharmacol, in press, Oct, 2000