The overall major goal of this proposal is to elucidate both the causes and effects of cannabidiol (CBD)-mediated inactivation of hepatic microsomal P450s 2C and 3A. The specific objectives include the continuation of the characterization of the chemical mechanisms of CBD-mediated P450 inactivation, with particular focus on those structural features of CBD implicated in P450 inactivation. Additional CBD analogs (modified mostly at the resorcinol moiety which appears to be critical for P450 inactivation) will be synthesized and examined. The mechanism by which two very closely related members of the P450 3A subfamily are differentially susceptible to CBD-mediated inactivation will also be investigated. Such marked differential susceptibility of constitutively expressed and steroid-inducible P450 3A isozymes to CBD-mediated inactivation win be assessed on the basis of differences in both structure and function. Accordingly, CBD metabolism by constitutive and steroid-inducible P450s 3A will be examined to determine its contribution to the differential susceptibility to CBD-mediated inactivation. In addition, differences in the active site structure of the enzymes will be explored to determine if altered partition ratios between product formation and enzyme inactivation contribute to the differential susceptibility of P450s 3A to CBD-mediated inactivation. The effects of CBD on the metabolism of other drugs of abuse will also be determined as an extension of those studies already undertaken on THC metabolism. Although the metabolism of many drugs of abuse has been extensively studied, their metabolic profiles after P450 inactivation remain to be elucidated. The appreciable CBD content in marijuana could alter the metabolism of other drugs of abuse frequently consumed with it. Our present sophistication in the categorization of P450s by their genetic subfamilies and function, should permit a rational basis for predicting the effect of inactivation of particular P450s on the well characterized metabolism of a certain drug. Thus, assignment of the metabolism of abused drugs to a given P450 subfamily would enable the prediction of the effects that P450 inactivation would have on its metabolism.
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