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 depressed hepatic uroporphyrinogen decarboxylase (URO-D) activity and accumulation of highly carboxylated porphyrins in the liver, was produced in 3 weeks in Fischer 344 rats. A single administration of a polychlorinated biphenyl mixture (Aroclor 1254) to iron-loaded female rats maintained continuously on delta-aminolevulinic acid supplemented drinking water produced the porphyric state. Without iron loading, URO-D activity appeared slightly less inhibited (33% of normal vs 23% of normal) but porphyrin accumulation was dramatically less (70 vs 605 micrograms porphyrin/g liver). Similar treatment in male rats produced URO-D activities of 54 and 70% of normal with and without iron loading, respectively, and porphyrin concentrations of 76 and 17 micrograms/g. When hexachlorobenzene was substituted for Aroclor 1254 treatment in female rats, URO-D activity was 61 and 69% of normal (with and without iron loading, respectively) and liver porphyrin concentrations were 96 and 25 micrograms/g, respectively. Hexachlorobenzene did not produce significant porphyric effects in male rats. Aroclor 1254 induced CYP1A to a greater extent in females than in males and to a greater extent than hexachlorobenzene, which showed a greater propensity to induce CYP2B. Overall correlation between 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 porphyria cutanea tarda.
Franklin
M R
MR
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City 84112, USA.
Phillips
J D
JD
Kushner
J P
JP
D000818:Animals; D001140:Aroclors / Q000633:toxicity; D020111:Chlorodiphenyl (54% Chlorine); D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction; D005260:Female; D005659:Fungicides, Industrial / Q000633:toxicity; D006581:Hexachlorobenzene / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D017119:Porphyria Cutanea Tarda / Q000139:chemically induced* / Q000378:metabolism*; D011166:Porphyrins / Q000378:metabolism* / Q000652:urine; D051381:Rats; D011916:Rats, Inbred F344; D012737:Sex Factors; D014575:Uroporphyrinogen Decarboxylase / Q000378:metabolism*
D001140:Aroclors; D005659:Fungicides, Industrial; D011166:Porphyrins; D020111:Chlorodiphenyl (54% Chlorine); D006581:Hexachlorobenzene; D003577:Cytochrome P-450 Enzyme System; D014575:Uroporphyrinogen Decarboxylase