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INVESTIGATIONS OF N-ACETYLTRANSFERASES IN HUMAN HEPATOCYTES AND RAT MODELS Jason M. Walraven March 4, 2005 This thesis begins by reviewing human N-acetyItransferases (Chapter I), then outlines experiments involving human hepatocytes and rat N-acetyltransferases (Chapters II-V). These experiments facilitated the development of a dissertation project designed to study Nacetyltransferase tissue-specific expression in inbred rat strains (Chapter VI). Real-time PCR experiments concluded that genetic and/or environmental factors influence N-acetyItransferase expression in cryopreserved human hepatocytes. Therefore, an animal model must be used to study N-acetyItransferase expression. Initial studies of recombinantly expressed rat N-acetyltransferases (Nats) revealed a correlation between rat and human N-acetyltransferases in nucleotide and amino acid sequence, catalytic activity, substrate selectivity and thermostability, suggesting the rat is an acceptable model for such studies. Dissertation aims outlined for studying rat N-acetyltransferase expression in tissues of various inbred rat strains involve analysis of tissue-specific mRNA splicing, mRNA expression, protein expression, and enzyme activity, and a study of cigarette smoke inhalation as a possible environmental influence on Nat expression.

Investigations of N-acetyltransferases in human hepatocytes and rat models.