Covalent binding metabolic pathway

The metabolic control is exercised on certain key regulatory enzymes of a pathway called allosteric enzymes. These are enzymes whose catalytic activity is modulated through non-covalent binding of a specific metabolite at a site on the protein other than the catalytic site. Such enzymes may be allosterically inhibited by ATP or allosterically activated by ATP (some by ADP and/or AMP). 

The metabolites 2- and 4-bromophenol can also be metabolized by a further oxidation pathway to yield catechols and quinones, some of which are cytotoxic and potentially hepa to toxic. Thus, in vitro studies have indicated that bromo quinones and bromocatechols may be responsible for some of the covalent binding to protein and reaction with GSH. 

With the exception of some anticancer drugs, chemicals directly toxic to tissues are eliminated in the drug development process, so drug toxicity involving covalent binding usually is mediated by chemically reactive metabolites. Current mechanistic understanding of these toxic reactions usually extends to identification of the reactive metabolite and metabolic pathway involved. In some cases, protective mechanisms for... 

A key focus of this chapter has been on the iminium/enamine stage of metabolism (figure 1) as the critical point governing the balance between toxic activation and detoxication pathways. Thus, although AO and MND efficiently intercept the -iminium derived from nicotine, PCP-Im is not a substrate for either enzyme. It seems quite significant that the lack of aldehyde oxidase substrate potential in this case correlates with increased levels of covalent binding of PCP relative to nicotine. 

As well as the formation of NAPQI there are various other possible metabolic pathways, including deacetylation and radical formation, which may or may not play a role in the hepatotoxicity. The importance of and interrelationships between covalent binding to particular hepatic proteins, cyclical oxidation and reduction of glutathione, oxidation of protein thiol groups and the intracellular calcium level are currently unclear. These events are not mutually exclusive and so it is possible that all are a series of necessary events occurring at particular stages in the development of paracetamol hepatotoxicity. However, covalent binding to protein is still believed to be the important event in the toxicity. 

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