Ability of several hexachlorobenzene metabolites to decrease rat-liver porphyrinogen carboxy-lyase and to produce...

Since hexachlorobenzene (HCB) action seems to be mediated through its metabolites, this study aimed to identify the metabolites and account for the HCB action by evaluating the ability of several of them to inhibit normal rat-liver porphyrinogen carboxy-lyase in vitro and to produce porphyrin accumulation in chick-embryo liver in ovo. Only three of the 11 metabolites assayed produced significant inhibitory effects at 10(-3) M concentration, the order being tetrachlorohydroquinone greater than pentachlorophenol much greater than pentachlorothiophenol. At concentrations below 10(-4) M tetrachlorohydroquinone did not inhibit the enzyme. Most of the metabolites assayed produced porphyrin accumulation, in the following order of strength: chlorophenols greater than chlorothiophenols greater than chlorobenzenes. Phenolic metabolites, therefore, not only produce the greatest amounts of porphyrin accumulation in the liver of the chick embryo but are also the strongest of the metabolite inhibitors of porphyrinogen carboxy-lyase in rat liver. It is possible that they decrease enzymatic activity by binding to the enzyme. This paper discusses the implications of these results for the mechanism of HCB porphyria induction.