Quinone reactive metabolites

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. 

FIGURE 8.15 Examples of quinone-typc reactive metabolites that can be viewed as Michael acceptors. 

Some metabolites, most commonly aromatic hydroxylamines and quinone-type metabolites, can undergo redox cycling and generate reactive oxygen species, especially... 

Toxicity by metabolism is not confined to the liver since oxidative systems occur in many organs and cells. Amodiaquine is a 4-aminoquinoline antimalarial that has been associated with hepatitis and agranulocytosis. Both side-effects are probably triggered by reactive metabolites produced in the liver or in other sites of the body. For instance polymorphonuclear leucocytes can oxidize amodiaquine. It appears that amodiaquine is metabolized to a quinone imine by the same pathway as that seen in... 

Another drug with a high incidence of hepatotoxicity is the acetylcholinesterase inhibitor tacrine. Binding of reactive metabolites to liver tissue correlated with the formation of a 7-hydroxy metabolite [13], highly suggestive of a quinone imine metabolite as the reactive species. Such a metabolite would be formed by further oxidation of 7-hydroxy tacrine (Figure 8.11). 

For example, epoxides, both aliphatic and aromatic, being chemically unstable are usually potentially reactive metabolites. Quinones and quinoneimines similarly are known to be able to react chemically with endogenous constituents of the cell. 

As already discussed in chapter 4, reactive intermediates can react with reduced GSH either by a direct chemical reaction or by a GSH transferase-mediated reaction. If excessive, these reactions can deplete the cellular GSH. Also, reactive metabolites can oxidize GSH and other thiol groups such as those in proteins and thereby cause a change in thiol status. When the rate of oxidation of GSH exceeds the capacity of GSH reductase, then oxidized glutathione (GSSG) is actively transported out of the cell and thereby lost. Thus, reduced GSH may be removed reversibly by oxidation or formation of mixed disulfides with proteins and irreversibly by conjugation or loss of the oxidized form from the cell. Thus, after exposure of cells to quinones such as menadione, which cause oxidative stress, GSH conjugates, mixed disulfides, and GSSG are formed, all of which will reduce the cellular GSH level. 

With chronic, higher level exposure, workers may suffer leukemia. Benzene is metabolized in the liver to a hydroquinone, which in the bone marrow is converted by the action of myeloperoxidase to the quinone and semiquinone products, which are reactive and therefore toxic. An unsaturated aldehyde, muconaldehyde is also a reactive metabolite, which could be involved in the toxicity (Fig. 6.29). 

Reactive metabolites include such diverse groups as epoxides, quinones, free radicals, reactive oxygen species, and unstable conjugates. Figure 8.2 gives some examples of activation reactions, the reactive metabolites formed, and the enzymes catalyzing their bioactivation. 

Kassahun K, Pearson PG, Tang W, et al. Studies on the metabolism of troglitazone to reactive metabolites in vitro and in vivo. Evidence for novel biotransformation pathways involving quinone methide formation and thiazolidine ring scission. Chem Res Toxicol 2001 14 62-70. 

Pan, S., Andrews, P.A., Glover, C.J., and Bachur, N.R., 1984, Reductive activation of mitomycin C and mitomycin C metabolites catalysed by NADPH-cytochorome P-450 reductase and xantine oxidase. J. Biol. Chem. 259 959-962 Pollakis, G., Goormaghtigh, E., and Ruysschaert, J.-M., 1983, Role of quinone structure in the mitochondrial damage induced by antitumor anthracyclines. FEBS Lett. 155 267-272 Rappaport, S.M., McDonald, T.A., and Yeowell-O Connell, K., 1996, The use ofprotein adducts to investigate the disposition of reactive metabolites of benzene. Environ. Health Perspect. 104Suppl6 1235-1237... 

Oxidation of deferiprone with hypochlorous acid, the major oxidant of neutrophil leukocytes, results in the formation of a chemically reactive species, consistent with the quinone metabolite of deferiprone. Deferiprone-related agranulocytosis presumably results from a T cell-mediated immunological reaction, induced by a reactive metabolite of deferiprone (18). In one case agranulocytosis and systemic vasculitis (with arthritis, palpable purpura of the legs, erythema of the palms and soles, and desquamation of the skin over the distal phalanges) occurred in association with deferiprone (22). 

Hemolytic anemia has been described for drugs containing sulfonamides, quinones, anilines, and carboxylic acids resulting from oxidative damage or covalent binding to red blood cells.42-49 NCEs with these functional groups should be carefully evaluated for reactive metabolite formation early in drug discovery. 

MetaDrug also includes 89 rules to predict likely reactive metabolites such as quinones, aromatic and hydroxyl amines, acyl glucuronides, acyl halides, epoxides, thiophenes, furans, phenoxyl radicals, phenols, and aniline radicals. Molecules with reactive groups are marked and highlighted. 

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. 

---