Multiple-drug activation enzyme

At least 10 metabolites have been identified, and some may be active. One may account for hepatotoxicity (4-ene-valproic acid), and it is increased by concurrent dosing with enzyme-inducing drugs. At least 67 cases of hepatotoxicity have been reported, and most deaths were in mentally retarded children less than 2 years old who were receiving multiple drug therapy. 

Moreover individuals were found who had multiple copies of the gene (up to 12 copies has been described in one Swedish family), and in these people a substance such as debrisoquine is metabolized so rapidly that virtually no therapeutic effect would be seen, as the hydroxy-metabolite is not pharmacologically active. These variants are inherited, and so it is possible to characterize families by their inherited drug-metabolizing enzymes, and the genes that code for them. 

The advent of highly active antiretroviral therapy (HAART) to minimize the rapid development of viral resistance in the treatment of HIV infection may result in multiple drug interactions (110-113). Both the nonnucleoside reverse transcriptase inhibitors and the protease inhibitors are substrates and inhibitors of some CYP enzymes, and some act as inducers as well (110,111). The major effects are on the CYP3A isoforms, and this has been used to advantage to increase concentrations of some HIV drugs. For example, delavirdine is a mechanism-based irreversible inhibitor of CYP3A4, and thereby is used to increase exposure to protease inhibitors (114). Ritonavir is a protease inhibitor, but it is used primarily for its ability as a potent inhibitor of CYP3A4 to increase concentrations of other protease inhibitors (115). 

Abstract This article provides a personal account of the discovery of the induced synthesis of drug-metabolizing enzymes and of subsequent research that led to the discovery of multiple cytochromes P450 with different catalytic activities. The manuscript also emphasizes the role of environmental factors (in addition to genetic polymorphisms) in explaining person-to-person and day-to-day differences in rates and pathways of drug metabolism that occur in the human population. 

In order to understand the selective toxicity of drugs such as PM and TM, and their significant differential activity between protozoa and bacteria, a brief discussion of multiple forms of enzymes is in order. 

Multiple sites of oxidation are frequently seen for substrates of drug metabolizing enzymes. This is likely to reflect either the capacity of the active site to bind the substrate in more than one orienta-tion/location or motion of substrate within the active site cavity. The former case is evident for the structure of CYP2C5 complex with DMZ,... 

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