CYP3A-inducing agents and the attenuation of uroporphyrin accumulation and excretion 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 (Aroclor 1254) into iron-loaded female Fischer 344 rats maintained continuously on delta-aminolevulinic acid-supplemented drinking water. In this model, daily treatment with 5-pregnen-3 beta-ol-20-one-16 alpha-carbonitrile (pregnenolone 16 alpha-carbonitrile) attenuated uroporphyrin and heptacarboxylporphyrin accumulation and excretion by 75%. Pregnenolone 16 alpha-carbonitrile treatment had only a minor effect on hepatic iron stores, and it had no effect on the induction of CYP1A activities by Aroclor 1254. In the absence of Aroclor 1254, pregnenolone 16 alpha-carbonitrile had no effect on the accumulation and excretion of highly carboxylated porphyrins. Attenuation of porphyrin accumulation could also be demonstrated with daily troleandomycin treatment. Troleandomycin increased CYP3A-dependent erythromycin demethylase activity, but to a lesser extent than pregnenolone 16 alpha-carbonitrile. Much of the CYP3A induced by troleandomycin was sequestered as a catalytically inactive metabolic-intermediate complex. In the absence of Aroclor 1254, troleandomycin had no effect on the accumulation and excretion of highly carboxylated porphyrins, nor did troleandomycin alter the induction of CYP1A by Aroclor 1254. The results suggest that the major attenuation of hepatic accumulation and urinary excretion of uro- and heptacarboxylporphyrins in the rat PCT model by pregnenolone 16 alpha-carbonitrile and troleandomycin is due to an enhancement of CYP3A catalytic activity.
Franklin
M R
MR
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USA. mfranklin@alanine.pharm.utah.edu
Phillips
J D
JD
Kushner
J P
JP
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000187:drug effects; D004195:Disease Models, Animal; D004790:Enzyme Induction; D005260:Female; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis* / Q000187:drug effects; D017119:Porphyria Cutanea Tarda / Q000378:metabolism*; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D014217:Troleandomycin / Q000494:pharmacology*; D014578:Uroporphyrins / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D014578:Uroporphyrins; D011285:Pregnenolone Carbonitrile; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating