All of these studies involve quantitative structure-activity analyses of pyrazole derivatives as probes of enzyme catalytic sites in vitro and as effectors of those enzymes within whole cells. This work began as an attempt to learn whether the properties of alcohol dehydrogenase determined with liver extracts have predictive value for that enzyme functioning in ethanol metabolism in vivo. The conclusions of that initial study had implications not only about alcohol dehydrogenase but also about the relative unimportance of other pathways of ethanol oxidation. However, those conclusions were potentially compromised by the demonstration in another laboratory that pyrazoles do, in contrast to long-standing assertions, inhibit microsomal ethanol oxidation. Thus, it became necessary to determine the structure-activity relationship for pyrazoles acting as ligands for cytochrome P450. That determination, in turn, suggested experiments with pyrazoles as inducers of P450 and the results of these experiments have provoked a working hypothesis about the unexplained mechanism of induction of some types of P450.
