Quinone metabolite

A large number of studies have investigated the metabolism of benzene per se or in relation to toxification and, particularly, myelotoxicity. Most evidence shows that benzene oxide (10.1, Fig. 10.8) is not the ultimate toxic species, as was initially believed. Indeed, phenol and quinone metabolites of benzene are more active in forming adducts with macromolecular nucleophiles and eliciting cellular toxicity. For example, the efficacy of benzene metabolites (see Fig. 10.8) to inhibit DNA synthesis in a mouse lymphoma cell line decreased in the order benzoquinone (10.17) > hydroquinone (10.16)... 

Like for benzene, the cytotoxicity of naphthalene is not due to the epoxide but to the quinone metabolites, namely 1,2-naphthoquinone and 1,4-naphthoquinone [85], As shown in Table 10.1, naphthalene 1,2-oxide (10.2) is a better substrate than benzene oxide for epoxide hydrolase. Its rapid isomerization to naphthalen-l-ol, facile enzymatic hydration to the dihydrodiol and lack of reactivity toward nucleophiles such as glutathione may explain its absence of direct toxicity [85],... 

Zhao, S.X. et al. (2007) NADPH-dependent covalent binding of [3H] paroxetine to human liver microsomes and S-9 fractions identification of an electrophilic quinone metabolite of paroxetine. Chemical Research in Toxicology, 20 (11), 1649-1657. 

Primaquine is the least toxic and most effective of the 8-aminoquinoline antimalarial compounds. The mechanism by which 8-aminoquinolines exert their antimalarial effects is thought to be through a quinoline-quinone metabolite that inhibits the coenzyme Q-mediated respiratory chain of the exoerythrocytic parasite. 

Hydroquinones. - 3,4-Dihydroxyphenylacetic acid, a metabolite of the neurotransmitter dopamine, has been shown to undergo oxidation by "NO to a semiquinone, which was observed by EPR upon spin stabilisation with Mg2+ ions.119 Formation of the radical may be a crucial event in the development of Parkinson s disease (section 18.3). 4-Hydroxyestradiol, which has been implicated in breast cancer, is oxidised to a semiquinone by HRP. Mutagenicity is believed to result from addition of the quinone metabolite to DNA.120... 

Study of the oxidation chemistry of exifone (25a) constitutes a perfect illustration of the above statement [59, 60]. This pyrogallol benzophenone (Adlone ) was commercialized in France for the treatment of cognitive disorders in the elderly, but it was withdrawn from the market because of its hepatotoxicity, which was attributed to its 3,4-quinone metabolite 26a. Fleury and co-workers found that blocking of 26 in the form of l,4-benzoxazin-8-one ortho-quinols such as 28 led to a twenty-fold decrease in toxicity, together with a five-fold activity enhancement (Figure 9) [59, 60]. 

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). 

Blackstaffe, L., Shelley, M. D., and Fish, R. G. (1997). Cytotoxicity of gossypol enantiomers and its quinone metabolite gossypolone in melanoma cell lines. Melanoma Res. 7,364-372. 

The activity of quinone reductase, a major protective enzyme, was increased 2-3-fold in first trimester human placental extracts in vitro when incubated for 6 hours with benz[a]anthracene. dibenz[a,h]anthracene, and chrysene at a concentration of 50 jmol (Avigdor et al. 1992). Based on these results, it can be postulated that the early placenta is capable of metabolizing certain toxic xenobiotics such as PAH quinone metabolites to inactive intermediates thereby protecting the developing embryo. 

Chaparral has also been associated with cystic renal disease in rats (Grice et al., 1968 Goodman et al., 1970 Evan et al., 1979) and humans (Smith et al., 1994 see Section 16.5). Toxicity studies revealed that cystic nephropathy could be reliably induced in rats fed a 2% by wt concentration of NDGA for 6 wk (Evan et al., 1979). Renal toxicity may stem from the accumulation of theo-quinone metabolite. NDGA is converted to this metabolite in the rat ileum and cecum, absorbed into the bloodstream, and excreted by the kidney, where it is reabsorbed by the epithelial cells of the proximal convoluted tubules. In the rat, tubular changes are thus confined to the tubules in the outer cortex (i.e., the proximal convoluted tubules) (Grice et al., 1968). 

Ether-extracted freeze-dried kidney tissue contained the o-quinone metabolite of NDGA, seen as red-brown granules. It was also seen as yellowbrown material in histiocytes, degenerating proximal tubular epithelium, small acellular casts, and occasionally in the cells lining the cysts and in the lumen of the proximal convoluted tubules. No free NDGA was found in the rat kidneys (Goodman et al., 1970). 

In rats, NDGA is metabolized in the lower third of the ileum and cecum to its o-quinone metabolite. It is absorbed into the bloodstream, is filtered by the glomeruli, then reabsorbed and retained by the proximal tubule epithelial cells... 

Burczynski, M.E., Harvey, R.G., and Penning, T.M. (1998) Expression and characterization of four recombinant human dihydrodiol dehydrogenase isoforms oxidation of trans-7,8-dihy-droxy-7,8-dihydrobenzo[a]pyrene to the activated o-quinone metabolite benzo[a] pyrene-7,8-dione. Biochemistry, 37, 6781-6790. 

Mechanism of action Primaquine forms quinoline-quinone metabolites, which are electron-transferring redox compounds that act as cellular oxidants. The drug is a tissue schizonticide and also limits malaria transmission by acting as a gametocide. 

Roy D, Bernhardt A, Strobel H, et al. Catalysis of the oxidation of steroid and stilbene estrogens to estrogen quinone metabolites by the 3-naphthotlavone-inducible cytochrome P450 1A family. Arch Biochem Biophys 1992 296 450-456. 

E. G., The catechol estrogen-3,4-quinone metabolites induce mutations in the mammary gland of ACI rats. Proc. Amer. Assoc. Cancer Res. 44(2nd ed.), 180 (2003). 

Multiple forms of cytochrome P-450 have differing catalytic activities with respect to formation of primary metabolites of BaP. Six different forms of cytochrome P-450 isolated from rabbit liver microsomes catalyzed the oxidation of BaP at different rates and produced different ratios of individual phenolic and quinone metabolites (572, 491). Different forms of cytochrome P-450 also showed differing activities and stereospecificity in metabolism of the —)-tranS 7,8-dihydrodiol to diol epoxides 101). The specificity of differing inducible forms of cytochrome P-450 in the metabolism of BaP is important since the predominance of a given form may influence the balance between activation and detoxification reactions. 

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