Sharon E. Murphy, Principal Investigator

Nitrosamines and P450s

Nicotine and related nitrosamines comprise a class of environmental carcinogens that requires metabolic activation to exert its carcinogenic potential. Enzymes of the cytochrome P450 family are responsible for this activation. Minor differences in nitrosamine structure lead to activation by different cytochrome P450s. Cytochrome P450s are found in all organisms from bacteria to mammals, and over 500 carrier deoxyribonucleic acid sequences have been identified. Most P450s are membrane bound and only recently have the first three-dimensional structures of mammalian P450s been published.

These researchers are using molecular modeling to determine the amino acids in the active site of cytochrome P450 2A enzymes important in substrate specificity. The P450 2A enzymes are very good at metabolizing nitrosamines, and understanding more about how very small differences in amino acid sequence can change the substrate specificity can help in understanding more about nitrosamine carcinogenesis.