INHIBITION OF PROSTAGLANDIN-H-SYNTHASE BY O-PHENYLPHENOL AND ITS METABOLITES

Chronic administration of o-phenylphenol (OPP) is known to induce urin ary bladder tumours in the Fischer rat. The underlying toxic mechanism is poorly understood. Recently, arachidonic acid (ARA)dependent, pros taglandin-H-synthase (PHS)-catalysed metabolic activation of the OPP m etabolite phenylhydroquinone (PHQ) to a genotoxic species was suggeste d to be involved in OPP toxicity. To investigate this hypothesis in mo re detail, we have studied the effects of OPP-and its metabolites on P HS. When microsomal PHS from ovine seminal vesicles (OSV) was used as enzyme source, both OPP, PHQ, and 2-phenyl-1,4-benzoquinone (PBQ) inhi bited PHS-cyclooxygenase. The inhibitory potency was inversely related to the ARA concentration in the assay; at 7 mu M ARA IC50-values were : 13 mu M (OPP), 17 mu M (PHQ), and 190 mu M (PBQ). In cells cultured from OSV, which express high PHS activity, 40 mu M OPP almost complete ly suppressed prostaglandin formation. Studies with microsomal PHS dem onstrated that PHQ was an excellent substrate for PHS-peroxidase; both ARA and hydrogen peroxide supported oxidation to PBQ. OPP was only a poor substrate for PHS, but inhibited the ARA-mediated and to a lesser extent also the hydrogen peroxide-mediated in vitro oxidation of PHQ. Moreover, PHQ at up to moderately cytotoxic concentrations (50 mu M) did not induce micronuclei in OSV cell cultures. Taken together, our f indings do not provide evidence for an ARA-dependent, PHS-catalysed fo rmation of genotoxic spe cies from PHQ. Moreover, it seems to be quest ionable whether such activation can effectively occur in vivo, since O PP and PHQ turned out to be efficient cyclooxygenase inhibitors, and h igh levels of OPP and PHQ were found at least in the urine of OPP-trea ted rats. On the other hand, inhibition of the formation of cytoprotec tive prostaglandins in the urogenital tract may play a crucial role in OPP-induced bladder carcinogenesis.