The long-term objective is to understand the impact of environmental chemicals on the olfactory system. The present proposal continues to explore the mechanisms of tissue-specific toxicity and molecular approaches to risk assessment in humans. Previous in vitro studies have indicated that nasal mucosa-predominant cytochrome P450 isoforms may be important in the olfactory epithelium-selective toxicity of many chemicals and that the regulation of these P450s may be controlled by tissue specific transcription factors which interact with unique DNA sequences in the promoter region of the P450 genes. The present specific aims are: (1). To generate knockout mice lacking Cyp2a5 or Cyp2g1 gene by homologous recombination; (2). To characterize Cyp2a5(-/-) and Cyp2g1(-/-) mice as models for studying the role of nasal P450s in microsomal metabolic activation and olfactory epithelium-selective toxicity of environmental chemicals; (3). To determine the role of a putative, conserved, nasal-predominant transcriptional activating (NPTA) element in the 5'-flanking region of rat CYP2A3 and human CYP2A6 genes in tissue-selective and developmental regulation of P450 gene expression using transgenic mice; and (4). To identify and characterize putative nasal-predominant transcription factors which bind to the NPTA element and activate transcription of CYP2A3 gene. Identification of the NPTA element and the NPTA factors will improve our understanding of the tissue-specific and developmental regulatory mechanisms for these and other genes expressed predominantly in the nasal mucosa. The knockout mice generated will be very useful for studying the role of CYP2A5 and CYP2G1 in the toxicity of numerous xenobiotics in the olfactory mucosa and adjacent tissues, such as the olfactory bulb, the pharynx, and the esophagus, which may be exposed to toxic metabolites originated from the olfactory mucosa. In future studies, possible correlations between genetic polymorphism of nasal-predominant P450 genes, including their regulatory sequences and transcription factors, with diseases of the head and neck area and the upper respiratory tract, such as nasopharyngeal tumors, nasal polyps, chronic nasal inflammation, asthma, and anosmia, will be explored.
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