Enzyme induction, molecular mechanisms

Two molecular mechanisms for the interactions have been established. First, both hypericin and hy-perforin, two of the pharmacologically active constituents of the herb, cause induction of the enzyme CYP3A4 which is responsible for much of the metabolism of many commonly used drugs. Giving SJW to patients also taking the immunosuppressant, cyclosporine, which is metabolized primarily by CYP3A4, has led to near-rejection of transplanted organs as cyclosporine plasma concentrations fell due to increased metabolism. The same mechanism has led to reduced efficacy of indinavir in patients... 

To better understand the health effects of plant phenolic compounds and to better utilize them, it is necessary to know the molecular mechanisms by which plant phenolic compounds induce cytoprotective enzymes. In vitro studies indicated that plant phenolic compounds such as curcumin often inhibited the enzymatic activities of GST, UGT, SULT as well as cytochrome P450s [Oetari et al., 1996], suggesting that the induction of cytoprotective enzyme activities could not be explained by direct interaction with plant phenolic compounds. On the other hand, much evidence indicates that the increased activity of cytoprotective enzymes are mainly attributable to enhanced transcriptional activation and enzyme synthesis [Holtzclaw et al., 2004]. 

Although less frequently compared with the reported cases of cytochrome P450 (CYP)-mediated dmg interactions, transporter-mediated dmg interactions have been reported in animals and humans. Unlike the CYP-mediated dmg interactions, which can be readily defined by inhibition or induction of CYP enzymes, the examples of transporter-mediated dmg interactions are often less conclusive (5-7). In many cases, transporter-mediated interactions are postulated on the basis of circumstantial evidence. Sometimes they are referred to as transporter-mediated dmg interactions because they cannot be explained by CYP inhibition or induction. Owing to the broad overlap in substrate specificity, many inhibitors and inducers can simultaneously affect both dmg transporters and CYP enzymes. Therefore, care should be exercised when exploring the underlying mechanisms of dmg interactions. The main purpose of this chapter is to explore the molecular mechanisms of dmg interactions involving dmg transporters. While the discussion will be focused predominantly on human data, examples from animal studies will also be used to assist in our understanding of the transporter-mediated dmg interactions. 

There have been reports of other glucagon actions in the liver which can be related to the elevation of cAMP, but whose molecular mechanisms are not well defined. Examples are the stimulations of ketogenesis, ureogenesis, amino acid transport, respiration and ion fluxes, the rapid changes in pyruvate dehydrogenase and pyruvate carboxylase, and the induction of P-enolpyruvate carboxykinase and other enzymes. 

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