Hydroquinone bioactivated

Subrahmanyam VV, Doane-Setzer P, Steinmetz KL, et al. 1990a. Phenol-induced stimulation of hydroquinone bioactivation in mouse bone marrow in vivo Possible implications in benzene myelotoxicity. Toxicology 62 107-116. 

Covalent protein adducts of quinones are formed through Mchael-type addihon reachon with protein sulfhydryl groups or glutathione. Metabolic activahon of several toxins (e.g., naphthalene, pentachlorophenol, and benzene) into quinones has been shown to result in protein quinone adducts (Lin et al, 1997 Rappaport et al, 1996 Zheng et al., 1997). Conversion of substituted hydroquinones such as p-aminophenol-hydroquinone and 2-bromo-hydroquinone to their respective glutathione S-conjugates must occur to allow bioactivation into nephrotoxic metabolites (Dekant, 1993). Western blot analysis of proteins from the kidneys of rats treated with 2-bromo-hydroquinone has revealed three distinct protein adducts conjugated to quinone-thioethers (Kleiner et al, 1998). 

Catechol may be oxidized by peroxidases to the reactive intennediate benzo-1,2-quinone, which readily binds to proteins (Bhat et al., 1988) this process, catalysed by rat or human bone-marrow cells in the presence of H2O2 (0.1 mM), is stimulated by phenol (0.1-10 mM), and decreased by hydroquinone and by glutathione, which conjugates with benzo-l,2-quinone. These phenols (phenol, catechol and hydroquinone) may play a role in benzene toxicity to bone marrow all three are formed as benzene metabolites (Smith et al., 1989) and they interact in several ways as far as their bioactivation by (myelo)peroxidases is concerned (Smith et al., 1989 Subrahmanyam et al., 1990). 

Chen and Eastmond (1995) showed that benzene metabolites can adversely affect human topoisomerases, enzymes involved in DNA replication and repair. No effect of any metabolite was seen on human topoisomerase I or for topoisomerase II for hydroquinone, phenol, 2,2 -biphenol, 4,4 -biphenol and catechol at concentrations as high as 500 pM. 1,4-Benzoquinone and 1,2,4-benzenetriol inhibited human topoisomerase II in vitro, at 500 and 250 pM without bioactivation. However, following bioactivation, phenol and 2,2 -biphenol showed inhibitory effects at doses as low as 50 pM, whereas 4,4 -biphenol inhibited topoisomerase II at concentrations of 10 pM. 

There is complete reduction of a p- or o-quinone to the corresponding hydroquinone or catechol, respectively. In the human liver, carbonyl reductase may play a role in the reduction of some quinones. Catechols are primary substrates for catechol o-me-thyl transferase, but also undergo sulfation. However, for the antitumor quinones, mitomycin C, adriamycin, and daunomycin, two-electron reduction serves as an efficient bioactivation mechanism, elegantly affirming the concept of bioreductive alkylation for the preferential bioactivation of antitumor prodrugs with oxygen deficient tumors. 

Isaacs, S., Hizi, A., and Kashman, Y. (1993) Toxicols A-C and toxiusol new bioactive hexaprenoid hydroquinones from Toxidona toxius. Tetrahedron, 49,4275-4282. 

---