EXPERIMENTAL AND CLINICAL PHARMACOGENETICS

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In the coming year we propose: a) to expand and further develop our computerized pharmacogenetic bibliographic data base on the University of Michigan Terminal Computer System; b) to continue to develop methodologies for identification and investigation of genetic factors which affect individual differences in the uptake of the antiarrhythmic drug, propranolol in leukocytes derived from humans and from animal models; c) to continue to develop high and low acetylator congenic strains of mice, and to continue acetylator phenotype determination of recombinant inbred strains of mice derived from A/J and C57BL/6J mice. We also plan to explore the basis for sex-related differences in extrahepatic (e.g., kidney) Na-acetyltransferase in these mouse strains and in androgen-insensitive (Tfm) mice. Survey of deacetylases activity for variation in inbred mouse strains will also be continued and a study of inheritance patterns of deacetylase variants will subsequently be undertaken in selected inbred mouse strains. Studies on inbred hamsters will be continued to investigate the inheritance pattern and pharmacological-toxicological significance of heritable N-acetyltransferase differences which have been identified; and d) to continue purification and biochemical characterization of human arylesterases and to test further the two-allele hypothesis of human arylesterase difference in human family pedigrees.