Uroporphyria produced in mice by 20-methylcholanthrene and 5-aminolaevulinic acid.
Iron-loaded male C57BL/6 mice allowed free access to an aqueous solution of 5-aminolaevulinic acid (ALA) (2 mg/ml) as their only drink, develop severe uroporphyria within 9 days of a single intraperitoneal dose of 20-methylcholanthrene (MC) (125 mg/kg). At 21 days, uroporphyrinogen decarboxylase (EC 4.1.1.37) activities are less than 10% of control activities. The porphyria is not dependent on pretreatment with iron and persists for at least 21 days after withdrawal of ALA. The same intraperitoneal dose of MC does not produce porphyria within 21 days when given without ALA. Continuous administration of ALA markedly accelerates the onset of porphyria in iron-loaded male C57BL/6 mice after a single intraperitoneal dose of hexachlorobenzene (200 mg/kg); mice given phenobarbitone and ALA do not become porphyric. MC with ALA does not produce porphyria in iron-loaded male DBA/2 mice. At least two separate events are needed to produce uroporphyria in mammals: induction of a specific form of cytochrome P-450 and stimulation of the formation of intermediates of haem biosynthesis in the liver. These results show that severe, persistent porphyria can be produced in mammals by compounds other than polyhalogenated aromatic hydrocarbons and suggest that a similar mechanism underlies the porphyrogenic action of halogenated and non-halogenated compounds.
Urquhart
A J
AJ
Department of Medical Biochemistry, University of Wales College of Medicine, Cardiff, U.K.
Elder
G H
GH
Roberts
A G
AG
Lambrecht
R W
RW
Sinclair
P R
PR
Bement
W J
WJ
Gorman
N
N
Sinclair
J A
JA
D000622:Aminolevulinic Acid / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006581:Hexachlorobenzene / Q000494:pharmacology; D007982:Levulinic Acids / Q000633:toxicity*; D008099:Liver / Q000187:drug effects; D008297:Male; D008748:Methylcholanthrene / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D010088:Oxidoreductases / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D011164:Porphyrias / Q000139:chemically induced*; D011166:Porphyrins / Q000378:metabolism; D014575:Uroporphyrinogen Decarboxylase / Q000378:metabolism; D014577:Uroporphyrinogens / Q000378:metabolism
D007982:Levulinic Acids; D011166:Porphyrins; D014577:Uroporphyrinogens; D006581:Hexachlorobenzene; D008748:Methylcholanthrene; D000622:Aminolevulinic Acid; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D014575:Uroporphyrinogen Decarboxylase; D010634:Phenobarbital