The decrease in uroporphyrinogen decarboxylase activity induced by ethanol predisposes rats to the development of porphyria and accelerates xenobiotic-triggered porphyria, regardless of hepatic damage.
We evaluated the porphyrinogenic ability of ethanol (20% in drinking water) per se, its effect on the development of sporadic porphyria cutanea tarda induced by hexachlorobenzene in female Wistar rats (170-190 g, N = 8/group), and the relationship with hepatic damage. Twenty-five percent of the animals receiving ethanol increased up to 14-, 25-, and 4.5-fold the urinary excretion of delta-aminolevulinate, porphobilinogen, and porphyrins, respectively. Ethanol exacerbated the precursor excretions elicited by hexachlorobenzene. Hepatic porphyrin levels increased by hexachlorobenzene treatment, while this parameter only increased (up to 90-fold) in some of the animals that received ethanol alone. Ethanol reduced the activities of uroporphyrinogen decarboxylase, delta-aminolevulinate dehydrase and ferrochelatase. In the ethanol group, many of the animals showed a 30% decrease in uroporphyrinogen activity; in the ethanol + hexachlorobenzene group, this decrease occurred before the one caused by hexachlorobenzene alone. Ethanol exacerbated the effects of hexachlorobenzene, among others, on the rate-limiting enzyme delta-aminolevulinate synthetase. The plasma activities of enzymes that are markers of hepatic damage were similar in all drug-treated groups. These results indicate that 1) ethanol exacerbates the biochemical manifestation of sporadic hexachlorobenzene-induced porphyria cutanea tarda; 2) ethanol per se affects several enzymatic and excretion parameters of the heme metabolic pathway; 3) since not all the animals were affected to the same extent, ethanol seems to be a porphyrinogenic agent only when there is a predisposition, and 4) hepatic damage showed no correlation with the development of porphyria cutanea tarda.
Ríos de Molina
M C
MC
Laboratorio de Porfirias Experimentales y Metabolismo del Hemo, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
Mazzetti
M B
MB
Galigniana
M
M
Aldonatti
C
C
Tomio
J M
JM
San Martín de Viale
L C
LC
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D004195:Disease Models, Animal; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D005294:Ferrochelatase / Q000187:drug effects* / Q000378:metabolism; D006581:Hexachlorobenzene; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D011162:Porphobilinogen / Q000652:urine; D000623:Porphobilinogen Synthase / Q000652:urine; D017119:Porphyria Cutanea Tarda / Q000139:chemically induced* / Q000201:enzymology / Q000652:urine; D011166:Porphyrins / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D012997:Solvents / Q000494:pharmacology*; D014575:Uroporphyrinogen Decarboxylase / Q000187:drug effects* / Q000378:metabolism
D011166:Porphyrins; D012997:Solvents; D000431:Ethanol; D006581:Hexachlorobenzene; D011162:Porphobilinogen; D003577:Cytochrome P-450 Enzyme System; D014575:Uroporphyrinogen Decarboxylase; D000623:Porphobilinogen Synthase; D005294:Ferrochelatase