EFFECTS OF PH ON NONENZYMATIC OXIDATION OF PHENYLHYDROQUINONE - POTENTIAL ROLE IN URINARY-BLADDER CARCINOGENESIS INDUCED BY O-PHENYLPHENOL IN FISCHER-344 RATS
Esc. Kwok et Da. Eastmond, EFFECTS OF PH ON NONENZYMATIC OXIDATION OF PHENYLHYDROQUINONE - POTENTIAL ROLE IN URINARY-BLADDER CARCINOGENESIS INDUCED BY O-PHENYLPHENOL IN FISCHER-344 RATS, Chemical research in toxicology, 10(7), 1997, pp. 742-749
o-Phenylphenol (OPP) and its sodium salt (SOPP) are broad spectrum fun
gicides and antibacterials to which humans are frequently exposed. Bot
h OPP and SOPP have been found to cause cancer in the urinary bladder
of male F344 rats at high doses, and the metabolite phenylhydroquinone
(PHQ) is believed to play a key role in the carcinogenicity of these
compounds. Tumor formation in the treated animals has also been shown
to be significantly influenced by urinary pH. To provide additional in
sights into the mechanisms of OPP carcinogenesis, we have investigated
the autoxidation of PHQ over the pH range commonly found in the urine
of OPP- and SOPP-treated rats. Over the pH range studied (6.3-7.6), a
curvilinear relationship between rate of PHQ oxidation and pH was obs
erved. Phenylbenzoquinone (PBQ) was formed during the autoxidation of
PHQ, with a formation yield of 0.92 +/- 0.02. In addition, the effects
of PBQ and oxygen concentrations on PHQ autoxidation and the nonenzym
atic conversion of PBQ to PHQ were also studied. Our data indicate tha
t the production of reactive metabolites from PHQ involves a pH-indepe
ndent (i.e., oxygen-dependent) and a pH-dependent pathway and that the
rate of pH-dependent PHQ autoxidation was found to be enhanced by the
presence of PBQ. A reaction mechanism has been formulated to explain
the experimental data observed, with ionization of PHQ semiquinone bei
ng identified as a key step in reactive species production for the pH-
dependent pathway. By combining data from OPP animal carcinogenicity s
tudies with the proposed reaction pathway, a good correlation between
the proposed formation of reactive species and bladder lesions was obs
erved. These results indicate that the pH-dependent autoxidation of fr
ee PHQ metabolite in the urine may potentially be responsible for the
tumorigenic effects of OPP and SOPP observed in the rat bladder.