Human enzymes of xenobiotic metabolism

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Human enzymes of xenobiotic metabolismXenobiotics are foreign chemicals such as drugs, carcinogens, and pollutants. Foreign compounds are metabolized in the human body in chemically remarkable ways. These metabolic processes, catalyzed by enzymes such as cytochrome P450 and glutathione transferase, can be crucial in determining the toxic effects of chemicals. Therefore, they are of great interest not only in biochemistry but also in the allied disciplines of pharmacology and toxicology. The central theme of Dr. Josephy's research is understanding the biochemistry of the enzymes that catalyze the metabolism of xenobiotics, with particular attention to their protein structures and catalytic functions. His lab. has brought together two different biotechnologies: bacterial mutagenicity assays and recombinant protein expression. In the new assay systems developed in Dr. Josephy's lab., E. coli bacteria are used to detect chemical mutagens, and they are also "taught" to metabolize foreign chemicals in the same ways that humans do. That is, human enzymes are expressed as recombinant proteins within the bacterial cells. This approach has led to increasingly reliable and relevant assays for toxic chemicals, and it also provides insight into the mechanisms of action of important human enzymes. The functional effects of naturally occurring variations in these human genes/enzymes, which are being discovered via genome sequencing projects, are now being studied. Another avenue of research is the "evolution", in the laboratory, of enzymes with altered sequences and catalytic activities. This aspect of the research program is pursued by randomly mutagenizing the gene encoding the enzyme, and then using the mutagenicity assay to screen libraries of mutants and identify ones with altered activities.