CYTOCHROME-P450 INDUCTION, UROPORPHYRINOGEN DECARBOXYLASE DEPRESSION,PORPHYRIN ACCUMULATION AND EXCRETION, AND GENDER INFLUENCE IN A 3-WEEK RAT MODEL OF PORPHYRIA-CUTANEA-TARDA

An experimental model of porphyria cutanea tarda, consisting of depres sed hepatic uroporphyrinogen decarboxylase (URO-D) activity and accumu lation of highly carboxylated porphyrins in the liver, was produced in 3 weeks in Fischer 344 rats. A single administration of a polychlorin ated biphenyl mixture (Aroclor 1254) to iron-loaded female rats mainta ined continuously on delta-aminolevulinic acid supplemented drinking w ater produced the porphyric state. Without iron loading, URO-D activit y appeared slightly less inhibited (33% of normal vs 23% of normal) bu t porphyrin accumulation was dramatically less (70 vs 605 mu g porphyr in/g liver). Similar treatment in male rats produced URO-D activities of 54 and 70% of normal with and without iron loading, respectively, a nd porphyrin concentrations of 76 and 17 mu g/g. When hexachlorobenzen e was substituted for Aroclor 1254 treatment in female rats, URO-D act ivity was 61 and 69% of normal (with and without iron loading, respect ively) and liver porphyrin concentrations were 96 and 25 mu g/g, respe ctively. Hexachlorobenzene did not produce significant porphyric effec ts in male rats. Aroclor 1254 induced CYP1A to a greater extent in fem ales than in males and to a greater extent than hexachlorobenzene, whi ch showed a greater propensity to induce CYP2B. Overall correlation be tween URO-D activity depression and porphyrin accumulation was highest when fitted to an exponential curve, indicating the importance of the extreme of the depression URO-D activity in evoking experimental porp hyria cutanea tarda. (C) 1997 Academic Press.