Studies on experimental hepatic porphyria.

Intraperitoneal administration of 3,5-diethoxy-carbonyl-1,4-dihydrocollidine (DDC) to female C3H/He/01a and NIH/01a inbred mice produced a marked dose-dependent loss of hepatic ferrochelatase (FK) activity, induction of g-aminolaevulinic acid synthetase (ALA-S) and accumulation of protoporphyrin. There was no strain difference in the degree of FK inhibition. However, induction of ALA-S was greater in C3H/He/01a mice. The strain difference in ALA-S response was most marked when inhibition of FK (the "specific" effect of DDC) was maximal and this suggests that a genetic variation exists in the sensitivity of ALA-S to a second, "non-specific" action of DDC, possibly related to its property of lipid-solubility. A sex difference in griseofulvin (GF)-induced porphyria was found with a greater hepatic protoporphyrin accumulation in male mice of all three strains examined. Stimulation of ALA-S activity was slightly greater in males, but when porphyria was very marked, ALA-S levels were significantly lower in this sex. These, and other, results demonstrated a two-way relationship between ALA-S activity and porphyrin accumulation, with a repression of ALA-S activity occuring at high liver protoporphyrin concentrations. Using a new method to add drugs in solution to cultures of chick embryo hepatocytes, the porphyrogenic effects of various drugs was compared. DDC and ISO-griseofulvin markedly inhibited FK activity and caused accumulation of protoporphyrin. In this system, ISO-griseofulvin was a more potent inhibitor of FK activity than either GF or HET-griseofulvin and also produced a greater accumulation of protoporphyrin, as previously reported in rodents. The hepatic green pigment accumulating in DDC, GF and ISO-griseofulvin-treated mice has been isolated, purified and identified as N-MePP, a previously established inhibitor of FK. All four possible structural isomers were demonstrated and each drug produced primarily the same isomer. An additional hepatic green pigment has been isolated from GF-treated mice, and spectral characteristics suggest this pigment is also an N-mono-substituted porphyrin, but its identity has not yet been established