Biochemical Studies on Griseofulvin‐Induced Protoporphyria

Shimoyama, Tokio; Nonaka, Shigeo

doi:10.1111/j.1749-6632.1987.tb48770.x

Cited by 9 publications

(3 citation statements)

References 9 publications

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“…Lifetime studies with griseofulvin, of similar duration to those in mice, in the rat and hamster have not shown the development of liver cancer and neither do these two species show the protoporphyria following shorter duration exposure 93. It is of note that the NOEL (approximately 0.1% in the diet) for griseofulvin induced liver enlargement and porphyria in mice111,112 is similar to the NOEL for tumor induction in mice (0.3% in the diet) 109. To complicate factors further, hepatocellular carcinomas have been reported to develop in male mice offspring suggesting that irreversible nuclear changes had occurred after as little as 21 days of exposure.…”

Section: Hepatic Tumours In Rodents Caused By Porphyria-inducing Chemmentioning

confidence: 96%

“…Even with potent AHR ligands hepatic neoplasia still appears to only occur at relatively high dose levels when saturation of the AHR binding and activation would be expected to occur. Indeed in experimental situations in rodents, the dose–response for neoplasia correlates best with elevations in liver weight above a threshold 109,111,112. The causes of the liver weight induction with these AHR agonists are also unlikely to be a simple product of sustained AHR activation since the “toxic hepatopathy” is far more likely to be the main driver for the chronic regenerative hepatic hyperplasia that is implicit in the AOP.…”

Section: An Adverse Outcome Pathway For Porphyria-induced Liver Cancementioning

confidence: 99%

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The association between chemical-induced porphyria and hepatic cancer

Smith

Foster²

2018

Toxicology Research

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The haem biosynthetic pathway is of fundamental importance for cellular metabolism both for the erythroid and nonerythroid tissues. There are several genetic variants of the pathway in the human population that cause dysfunction of one or other of the enzymes resulting in porphyrias of varying severity. Serious chronic hepatic and systemic diseases may result. Some of these can be precipitated by exposure to drugs including hormones, barbiturates and antibiotics, as well as alcohol and particular chlorinated aromatic chemicals. In experimental animals some of the steps of this pathway can also be severely disrupted by a variety of environmental chemicals, potential drugs and pesticides, especially in the liver, leading to the accumulation of uroporphyrins derived from the intermediate uroporphyrinogens or protoporphyrin IX, the immediate precursor of haem. With some of these chemicals this also leads to cholestasis and liver cell injury and eventually hepatic tumours. The review evaluates the available evidence linking hepatic porphyria with carcinogenesis in naturally occurring human genetic conditions and in chemically-induced porphyrias in laboratory animals. The existing data showing gender, strain, and species differences in sensitivity to the chemical-induced porphyrias, liver injury and liver tumours are discussed and the role that transgenically altered mouse models have played in defining the varying mechanisms. Finally, the review proposes a novel, unifying hypothesis linking the hepatotoxicity induced by the accumulation of various porphyrins, with the increased risk of developing hepatic cancer as a long term consequence.

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Section: Hepatic Tumours In Rodents Caused By Porphyria-inducing Chemmentioning

confidence: 96%

Section: An Adverse Outcome Pathway For Porphyria-induced Liver Cancementioning

confidence: 99%

The association between chemical-induced porphyria and hepatic cancer

Smith

Foster²

2018

Toxicology Research

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“…Experimental protoporphyria can be induced in mice by administration of feed containing high concentrations of griseofulvin (GF) (1,2). The pathomechanism of protoporphyria is related to the suppression of heme synthetase activity (3), which causes increases in the amount of protoporphyrin (PI') in the liver and erythrocytes of the mice. The most Liver, feces (1.0~2.0 g) A mixture of ethyl acetate and glacial acetic acid (3:1 v/v) is added (30 ml) and homogenized with a polytron homogenizer (Type PT 10 ..... Fig.…”

Section: Introductionmentioning

confidence: 99%

Experimental Murine Protoporphyria Induced by Griseofulvin (GF): The Relationship between Hepatic Porphyrin Levels and Liver Function Test Values in Mice Treated with GF

Tanaka

Ohgami

Nonaka

1993

The Journal of Dermatology

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To investigate the hepatic abnormalities accompanying experimental protoporphyria due to griseofulvin (GF), liver function test values and porphyrin levels in mice were assayed at days 2, 4, 8, and 16 after starting the administration of 0.5% GF feed. Furthermore, in an attempt to elucidate the harmful effects of GF on liver functions, the above mentioned assay was also performed after the feed was discontinued in mice given 0.5% GF feed for 16 days. The hepatic protoporphyrin (PP) level had already risen by day 2, but the erythrocytic PP level was within normal limits at that time. Hepatic PP levels increased gradually, followed by an increase in erythrocytic PP levels. The variation in liver function test values roughly paralleled the porphyrin levels. Over the time span of the response to GF, the variations in the serum glutamate oxaloacetate transaminase (S-GOT) levels, serum glutamate pyruvate transaminase (S-GPT) levels, and leucine amino peptidase (LAP) levels resembled those in hepatic PP. On the other hand, the changes in alkaline phosphatase (ALP) levels paralleled those of the erythrocytic PP levels. Erythrocytic and fecal protoporphyrin levels decreased to the normal level one month after the discontinuation of GF administration, but the hepatic protoporphyrin level still was 53.6 times higher than the normal level two months after switching to normal feed. The values of liver function tests had returned to within the normal range after one month. By the fourth day after the administration of GF, a brown pigmented material could be observed around the hepatocytes and the Glisson sheath; the amount of this material increased day by day.(ABSTRACT TRUNCATED AT 250 WORDS)

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Preclinical Safety Testing and Assessment of Veterinary Pharmaceuticals and Pharmacovigilance

Woodward¹

2009

Veterinary Pharmacovigilance

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Biochemical Studies on Griseofulvin‐Induced Protoporphyria

Cited by 9 publications

References 9 publications

The association between chemical-induced porphyria and hepatic cancer

The association between chemical-induced porphyria and hepatic cancer

Experimental Murine Protoporphyria Induced by Griseofulvin (GF): The Relationship between Hepatic Porphyrin Levels and Liver Function Test Values in Mice Treated with GF

Preclinical Safety Testing and Assessment of Veterinary Pharmaceuticals and Pharmacovigilance

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