CYP3A-inducing agents and the attenuation of uroporphyrin accumulation andexcretion in a rat model of porphyria cutanea tarda

An experimental model of porphyria cutanea tarda (PCT) can be achieved in 3 weeks by a single injection of a mixture of polychlorinated biphenyls (Aro clor 1254) into iron-loaded female Fischer 344 rats maintained continuously on delta-aminolevulinic acid-supplemented drinking water. In this model, d aily treatment with 5-pregnen-3 beta-ol-20-one-16 alpha-carbonitrile (pregn enolone 16 alpha-carbonitrile) attenuated uroporphyrin and heptacarboxylpor phyrin accumulation and excretion by 75%. Pregnenolone 16 alpha-carbonitril e treatment had only a minor effect on hepatic iron stores, and it had no e ffect on the induction of CYP1A activities by Aroclor 1254. In the absence of Aroclor 1254, pregnenolone 16 alpha-carbonitrile had no effect on the ac cumulation and excretion of highly carboxylated porphyrins. Attenuation of porphyrin accumulation could also be demonstrated with daily troleandomycin treatment. Troleandomycin increased CYP3A-dependent erythromycin demethyla se activity, but to a lesser extent than pregnenolone 16 alpha-carbonitrile . Much of the CYP3A induced by troleandomycin was sequestered as a catalyti cally inactive metabolic-intermediate complex. In the absence of Aroclor 12 54, troleandomycin had no effect on the accumulation and excretion of highl y carboxylated porphyrins, nor did troleandomycin alter the induction of CY P1A by Aroclor 1254. The results suggest that the major attenuation of hepa tic accumulation and urinary excretion of uro- and heptacarboxylporphyrins in the rat PCT model by pregnenolone 16 alpha-carbonitrile and troleandomyc in is due to an enhancement of CYP3A catalytic activity. (C) 2000 Elsevier Science Inc.