Catechol reactive metabolites

A relatively unique type of reactive metabolite is carbene, i.e., a divalent carbon, which is a proposed intermediate in the oxidation of methylene dioxy-containing compounds. A methylenedioxy group in aromatic compounds is subject to O-dealkylation, e.g., 3,4-methylenedioxyamphetamine, as shown in Figure 8.20. The process generates formic acid and the catechol metabolite as final products. However, in the course of the reaction, a... 

In the subsequent years, a number of other monohydroxy- A1-THC derivatives have been isolated from various metabolizing systems (Figure 2). These have been of two types hydroxyls allylic to the M-double bond and sidechain hydroxyls. No evidence for aromatic hydroxylation has thus far been reported, although these positions are chemically reactive and there is biochemical evidence for C-C glucuronide formation at the 4 -position of A6-THC. Possibly such catechol type metabolites of A1-THC are unstable and may be lost during the extraction and isolation procedures. 

Capsaicin and capsaicinoids undergo Phase I metabolic bioconversion to catechol metabolites via hydroxylation of the vanillyl ring moiety (Lee and Kumar, 1980 Miller et al, 1983). Metabohsm involves oxidative, in addition to non-oxidative, mechanisms. An example of oxidative conversion involves the liver mixed-function oxidase system to convert capsaicin to an electrophilic epoxide, a reactive metabolite (Olajos, 2004). Surh and Lee (1995) have also demonstrated the formation of a phenoxy radical and quinine product the quinine pathway leads to formation of a highly reactive methyl radical (Reilly et al, 2003). The alkyl side chain of capsaicin also undergoes rapid oxidative deamination (Wehmeyer et al, 1990) or hydroxylation (Surh et al, 1995 Reilly et al, 2003) to hydroxycapsaicin as a detoxification pathway. An example of nonoxidative metabolism of capsaicin is hydrolysis of the acid-amide bond to yield vanillylamide and fatty acyl groups (Kawada et al, 1984 Oi et al, 1992). 

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). 

Dihydrodiols are seldom observed, as are catechol metabolites produced by their dehydrogenation, catalyzed by dihydrodiol dehydrogenase. The further oxidation of phenols and phenolic metabolites to a catechol or hydro-quinone is also possible, the rate of reaction and the nature of products depending on the ring and on the nature and position of its substituents. In a few cases, catechols and hydroquinones have been found to undergo further oxidation to quinones by two single-electron steps. The intermediate in this reaction is a semiquinone. Both quinones and semiquinones are reactive, in particular toward biomolecules, and have been implicated in many toxitication reactions. For example, the high toxicity of benzene in bone marrow is believed to be due to the oxidation of catechol and hydroquinone catalyzed by myeloperoxidase. 

Sasame, H.A., Ames, M.M. and Nelson, S.D. (1977) Cytochrome P-450 and NADPH-cytochrome c reductase in rat brain formation of catechols and reactive catechol metabolites. Biochem. Biophys. Res. Commun. 78 919-926. 

---