Metabolite reactive

Mechanisms of Cardiotoxicity Chemical compounds often affect the cardiac conducting system and thereby change cardiac rhythm and force of contraction. These effects are seen as alterations in the heart rate, conduction velocity of impulses within the heart, and contractivity. For example, alterations of pH and changes in ionic balance affect these cardiac functions. In principle, cardiac toxicity can be expressed in three different ways (1) pharmacological actions become amplified in an nonphysiological way (2) reactive metabolites of chemical compounds react covalently with vital macromolecules... 

Several chemical compounds may cause inflammation or constriction of the blood vessel wall (vasoconstriction). Ergot alkaloids at high doses cause constriction and thickening of the vessel wall. Allylamine may also induce constriction of coronary arteries, thickening of their smooth muscle walls, and a disease state that corresponds to coronary heart disease. The culprit is a toxic reactive metabolite of allylamine, acrolein, that binds covalently to nucleophilic groups of proteins and nucleic acids in the cardiac myocytes. 

Glucose- 6-phosphate dehydrogenase Low or absent enzyme activity in about 10% of African populations. Hemolysis following intake of a number of drugs which have electrophilic reactive metabolites, but also, carriers of this enzyme deficiency have a partial protection from malaria. 

There is strong evidence that DNA adduction by these bulky reactive metabolites of PAHs is far from random, and that there are certain hot spots that are preferentially attacked. Differential steric hindrance and the differential operation of DNA repair mechanisms ensure that particular sites on DNA are subject to stable adduct formation (Purchase 1994). DNA repair mechanisms clearly remove many PAH/ guanine adducts very quickly, but studies with P postlabeling have shown that certain adducts can be very persistent—certainly over many weeks. Evidence for this has been produced in studies on fish and Xenopus (an amphibian Reichert et al. 1991 Waters et al. 1994). 

Figure 53-1. Simplified scheme showing how metabolism of a xenobiotic can result in cell injury, immunologic damage, or cancer. In this instance, the conversion of the xenobiotic to a reactive metabolite is catalyzed by a cytochrome P450,and the conversion of the reactive metabolite (eg, an epoxide) to a nontoxic metabolite is catalyzed either by a GSH S-transferase or by epoxide hydrolase.

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. 

These experiments provide evidence that DA and/or its reactive metabolites are likely involved in MDMA-induced changes in the serotonergic system. When DA synthesis was inhibited with MT, or when DA innervation was interrupted by 6-OHDA lesions, the effects of MDMA were prevented or attenuated. Depletion of DA with reserpine, or inhibition of DA uptake with GBR 12909, also attenuated the effects of MDMA on the serotonergic system. 

It is premature to define the exact mechanism by which DA is involved in the response to METH or MDMA. It is known- that these drugs release large quantities of DA and that DA can be readily oxidized to reactive metabolites, which could possibly cause destruction of nerve terminals (Graham 1978 Maker et al. 1986). Moreover, these effects could be enhanced by inhibition of monoamine oxidase, which is known to occur with these drugs (Susuki et al. 1980). The possibility that 6-DOHA is formed and subsequently destroys the nerve terminals, as suggested by Seiden and Vosmer (1984), also requires investigation. 

I think the results are compatible with the idea that Dr. Seiden has, that it is 6-hydroxydopamine. I think that it could be a 6-hydroxydopamine or some other reactive metabolite of dopamine that is causing the effect. 

Reactive Metabolite Formation, Mechanism-Based CYP Inhibition,... 

The presence of chemically reactive structural features in potential drug candidates, especially when caused by metabolism, has been linked to idiosyncratic toxicity [56,57] although in most cases this is hard to prove unambiguously, and there is no evidence that idiosyncratic toxicity is correlated with specific physical properties per se. The best strategy for the medicinal chemist is avoidance of the liabilities associated with inherently chemically reactive or metabolically activated functional groups [58]. For reactive metabolites, protein covalent-binding screens [59] and genetic toxicity tests (Ames) of putative metabolites, for example, embedded anilines, can be employed in risky chemical series. 

The search for an alternative reactive metabolite for the polycyclic hydrocarbon carcinogens was soon successful. Also in 1973, Borgen et al. (54) reported that, in the presence of a microsomal system from hamster liver, trans 7,8-dihydro-7,8-dihydroxybenzola]-pyrene (a metabolite of benzo[aJpyrene) was bound to DNA in vitro some ten times more extensively than was benzo[a]pyrene itself. 

Reactive Metabolites of PAHs. A wide variety of products have been identified as metabolites of PAHs. These include phenols, quinones, trans-dihydrodiols, epoxides and a variety of conjugates of these compounds. Simple epoxides, especially those of the K-region, were initially favored as being the active metabolites responsible for the covalent binding of PAH to DNA. Little direct experimental support exists for this idea (62.63,64) except in microsomal incubations using preparation in which oxidations at the K-region are favored (65,66). Evidence has been presented that a 9-hydroxyB[a]P 4,5-oxide may account for some of the adducts observed in vivo (67.68) although these products have never been fully characterized. 

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