Metabolite chemically reactive

Allemand H, Pessayre D, Descatoire V, et al. 1978. Metabolic activation of trichloroethylene into a chemically reactive metabolite toxic to the liver. J Pharmacol Exp Ther 204 714-723. 

Gillette, J.R. 1994. Commentary. Perspective on the role of chemically reactive metabolites of foreign compounds in toxicity. I. Correlation of changes in covalent binding of reactivity metabolites with changes in the incidence and severity of toxicity. Biochem. Pharmacol. 23, 2785. 

Irreversible CYP inhibition, especially when considered as a cause of chemically reactive metabolites, raises a number of issues that should be considered early in the drug discovery process. Careful evaluation of the structural features of the lead series as well as screening for MBIs early in the drug development process should guide series selection and optimization with the goal of avoiding the introduction of potentially risky moieties into new chemical entities. 

Castagnoli, N. and Castagnoli, K.P. (1993) Biotransformation of xenobiotics to chemically reactive metabolites, in Drug Toxicokinetics. Drug and Chemical Toxicology Series vol. 9 (eds P.G. 

Boyd MR, Burka LT. In vivo studies on the relationship between target organ alkylation and the pulmonary toxicity of a chemically reactive metabolite of 4-ipomeanoI. J Pharmacol Exp Ther 1978 207(3) 687-697. 

These studies demonstrated that DNA-binding can be a reliable probe of metabolic activation. In contrast to studies of metabolites per se, which usually involve large numbers of metabolite intermediates, DNA-binding monitors only chemically reactive metabolites. Also, if there is no selective repair of specific adducts, DNA-binding monitors the cumulative production of metabolites over time, while direct measurement of metabolites can show the metabolite spectrum only at the time observed. This can be particularly critical for studies of activation of complex chemicals such as polycyclic aromatic hydrocarbons whose primary metabolites are subject to secondary and tertiary metabolism (8). 

Metabolism, primarily in the liver, can sometimes yield a product that is chemically reactive. Although generally the liver can detoxify such metabolites, if the amount is excessive these detoxification processes can be overwhelmed. When this happens the chemically reactive metabolite can react with constituents of the cells in which they are produced. This can cause damage to important molecules such as DNA or structures inside the cell, which can lead to the death of the cell. 

The aflatoxins are a group of related mycotoxins produced by the mould Aspergillus flavus. There are four toxins, B, B2, G, and G2. The mould typically grows on crops such as grain and peanuts in hot, humid climates. There is evidence from epidemiology of an association between exposure to aflatoxin Bi in the diet and liver cancer in humans. Aflatoxin Bj is metabolized by the enzyme system cytochrome P450 in the liver to a chemically reactive metabolite (see pp. 19-23 and fig. 25), which reacts with molecules such as DNA and protein in liver cells. 

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... 

Administration of bromobcnzcnc to rats causes severe liver necrosis. Extensive in vivo and in vitro studies indicate that the liver damage results from the interaction of a chemically reactive metabolite, 4-bromobcnzcnc oxide, with hcpatocytcs. " Extensive covalent binding to hepatic tissue... 

Symposium on Formation of Chemically Reactive Metabolites as a Cause of Drug Toxicity, New Orleans, August 15-19, 1976, Pharmacologist, 18, 108(1976). 

Park BK, Boobis A, Clarke S (2011) Managing the challenge of chemically reactive metabolites in drug development. Nat Rev Drug Discov 10 292-306... 

The discussion that follows focuses on selected examples of metabolic transformations that may be linked to the formation of potentially neurotoxic metabolites. Although the number of well-characterized examples of such biotransformations is relatively few, it may be reasonable to speculate that the neurological disorders associated with long-term exposure to substances of abuse and some behaviormodifying medications may involve biochemical lesions mediated by chemically reactive metabolites. Thus, it may be important when attempting to assess the possible significance of metabolic bioactivation processes to appreciate that the chemical instability of reactive metabolites which can make the identification and characterization of their biological properties difficult. 

It therefore is necessary to identify targets for these reactive metabolites (i.e., covalently modified macromolecules) that are critical to the toxicological process. Hard electrophiles generally react with hard nucleophiles, such as the basic groups in DNA and lysine u-amino residues in proteins. Soft electrophiles react with soft nucleophiles, which include cysteine residues in proteins and in glutathione. Unfortunately, no simple rules predict the target macromolecules tor a particular chemically reactive metabolite or the biological consequences of a particular modification. Furthermore, noncovalent interactions also ... 

Several enzyme systems exist as cellular defense (detoxification) pathways against the chemically reactive metabolites generated by GYP metabolism (91,92,102,103). These include GST, epoxide hydrolase, and quinone reductase, as well as catalase, glutathione peroxidase, and superoxide dismutase, which detoxify the peroxide and superoxide by-products of metabolism. The efficiency of the bioinactivation process is dependent on the inherent chemical reactivity of the electrophilic intermediate, its affinity and selectivity of the reactive metabolite for the bioinactivation enzymes, the tissue expression of these enzymes, and the rapid upregulation of these enzymes and cofactors mediated by the cellular sensors of chemical stress. The reactive metabolites that can evade these defense systems may damage target proteins and nucleic acids by either oxidation or covalent modification. 

Williams DP, Kitteringham NR, Naisbitt DJ, et al. Are chemically reactive metabolites responsible for adverse reactions to drugs Curr Drug Metab 2002 3 351-366. 

Gillette JR. The problem of chemically reactive metabolites. Drug Metabolism Reviews 1982 13 941-961. 

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