A Biochemical Study of Experimental Porphyria

Abstract

In order to determine the lowest concentration of griseofulvin (GF) needed to induce abnormal porphyrin metabolism, D‐D strain mice were fed with a feed containing GF in concentrations of 0.1%, 0.5%, and 1.0%. The liver and blood porphyrin levels were analyzed, and the red fluorescence of the liver and blood observed with a fluorescent microscope. In the 0.5% GF and 1.0% GF groups, a swelling of the liver was observed, and coproporphyrin and protoporphyrin levels in the liver and the blood increased markedly. However, the increase in protoporphyrin levels was more prominent than the increase of coproporphyrin levels. The increase in the liver protoporphyrin was more marked than that in the blood porphyrin. Comparisons of the 0.5% GF and 1.0% GF groups revealed that liver swelling was more prominent in the 1.0% GF group. A high degree of metabolic abnormality in blood protoporphyrin was found in 1.0% GF animals whose feeding period was rather short. In the 0.1% GF group, liver swelling was hardly noticeable, and there were no differences between the short feeding and long feeding groups. Although no abnormalities in blood porphyrins were noticed in comparison with the normal group, abnormally high levels of liver porphyrins were found in 3 out of the 34 treated mice. No differences from the normal group were noted in the remaining 31 animals. In the 0.5% GF and 1.0% GF groups, red fluorescence of the liver was seen in all cases, while in the 0.1% GF group, reticular red fluorescence was noted in only one animal. From these findings, it appears that a marked increase in porphyrin occurs at a concentration above 0.5% in D‐D strain mice, whereas, at the concentration of 0.1%, the majority of the treated mice remain within normal limits. Only a few showed any abnormality of porphyrin metabolism. We feel that, for this reason, it would be better to use a GF concentration of 0.1% for the lowest concentration experiments involving GF‐induced protoporphyria in D‐D strain mice and especially for investigations of the interaction of other chemicals with GF, and investigations of initial changes of porphyrin metabolism.

The association between chemical-induced porphyria and hepatic cancer

“…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.…”

“…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.…”