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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM027028-08
Application #
3096078
Study Section
Pharmacology-Toxicology Review Committee (PTR)
Project Start
1980-01-01
Project End
1990-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
8
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Voice, R A; Manis, M; Weber, W W (1993) Inhibition of human red blood cell N-acetyltransferase. Drug Metab Dispos 21:181-3
Smolen, T N; Brewer, J A; Weber, W W (1993) Testosterone modulation of N-acetylation in mouse kidney. J Pharmacol Exp Ther 264:854-8
Martell, K J; Weber, W W (1993) N-acetylation polymorphism in liver and pancreas of inbred rats. Drug Metab Dispos 21:965-6
Weber, W W; Vatsis, K P (1993) Individual variability in p-aminobenzoic acid N-acetylation by human N-acetyltransferase (NAT1) of peripheral blood. Pharmacogenetics 3:209-12
Adkins, S; Gan, K N; Mody, M et al. (1993) Molecular basis for the polymorphic forms of human serum paraoxonase/arylesterase: glutamine or arginine at position 191, for the respective A or B allozymes. Am J Hum Genet 52:598-608
Levy, G N; Weber, W W (1992) 2-Aminofluorene-DNA adducts in mouse urinary bladder: effect of age, sex and acetylator phenotype. Carcinogenesis 13:159-64
Bartels, C F; Jensen, F S; Lockridge, O et al. (1992) DNA mutation associated with the human butyrylcholinesterase K-variant and its linkage to the atypical variant mutation and other polymorphic sites. Am J Hum Genet 50:1086-103
Bartels, C F; James, K; La Du, B N (1992) DNA mutations associated with the human butyrylcholinesterase J-variant. Am J Hum Genet 50:1104-14
Jensen, F S; Bartels, C F; La Du, B N (1992) Structural basis of the butyrylcholinesterase H-variant segregating in two Danish families. Pharmacogenetics 2:234-40
Martell, K J; Vatsis, K P; Weber, W W (1991) Molecular genetic basis of rapid and slow acetylation in mice. Mol Pharmacol 40:218-27

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