Relative Potencies of Polychlorinated Dibenzo-p-dioxins, Dibenzofurans, and Biphenyls Derived from Hepatic Porphyrin Accumulation in Mice

Abstract

Hepatic porphyrin accumulation was studied after subchronic dosing of female B6C3F1 mice by gavage with single congeners of polychlorinated or polybrominated dibenzo-p-dioxins (PCDDs, PBDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs). Quantitative hepatic porphyrin profile analyses in selected samples showed uroporphyrin and heptacarboxylporphyrin as the main porphyrins detected. Dose-dependent increases in total hepatic porphyrins were found for all congeners tested. At lower dose levels, relative potencies, based on administered dose as well as target tissue dose, of PCDDs, PCDFs, and coplanar PCBs, using 2,3,7,8-tetrachlorodibenzo-p-dioxin as a reference compound, were in the same range as those previously derived from the induction of hepatic CYP1A1 and CYP1A2 enzyme activities. CYP1A2 has been reported to be involved in the oxidation of uroporphyringen III to uroporphyrin III. All these facts suggest the involvement of an aryl hydrocarbon receptor-mediated mechanism in hepatic porphyrin accumulation, possibly via CYP1A2. However, the relative potencies of the mono-ortho-substituted PCBs were higher for hepatic porphyrin accumulation than for hepatic CYP1A1 and CYP1A2 induction. In addition, hepatic porphyrin accumulation was the highest after exposure to mono-ortho-PCBs. Since mono-ortho-substituted PCBs induce the phenobarbital-inducible CYP2B isoforms of cytochrome P450, an additional induction of δ-aminolevulinic acid synthetase may also contribute to hepatic porphyrin accumulation following subchronic exposure to these particular congeners. Relative potencies derived from hepatic porphyrin accumulation after PCDD, PCDF, or coplanar PCB administration are a useful tool in risk assessment. However, the higher relative potencies of the mono-ortho-substituted PCBs have important implications for risk assessment of these compounds.