STRAIN AND SEX-DIFFERENCES IN THE RESPONSE OF MICE TO DRUGS THAT INDUCE PROTOPORPHYRIA - ROLE OF PORPHYRIN BIOSYNTHESIS AND REMOVAL

A hepatic green pigment, inhibitory toward ferrochelatase, has been isolated from the liver of mice treated with griseofulvin, isogriseofulvin, or 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine and has been shown to exhibit identical chromatographic characteristics to authentic N‐methyl protoporphyrin. All four possible structural isomers have been demonstrated, and each drug produced primarily the same isomer. N‐Methyl protoporphyrin has also been found in very small amounts in the liver of untreated mice, but the isomeric composition appeared to differ from that of the drug‐induced N‐methyl protoporphyrin. Intraperitoneal administration of 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine to female C3H / He / Ola and NIH / Ola inbred mice produced a marked dose‐related loss of hepatic ferrochelatase activity, which was identical in magnitude in the two strains. Induction of hepatic 5‐aminolevulinate synthase (ALA‐S), and accumulation of liver protoporphyrin, however, were greater in C3H / He / Ola mice. The strain difference in ALA‐S response was most marked when inhibition of ferrochelatase (the “specific” effect of the drug) was maximal, and this suggests that a genetic variation exists in the sensitivity of ALA‐S to a second drug action, the so‐called nonspecific action, which is shared by many lipid‐soluble compounds. Male mice of three strains accumulated greater amounts of hepatic protoporphyrin than females after treatment with griseofulvin, yet no significant difference was found between the two sexes in the extent of ferrochelatase inhibition. Stimulation of ALA‐S activity was slightly greater in males, but when porphyria was very marked, ALA‐S activities were significantly lower in this sex. Our results indicate a biphasic relationship between ALA‐S activity and porphyrin accumulation, with a depression of the activity of the enzyme occurring at high liver protoporphyrin concentrations. Copyright © 1990 Wiley‐Liss, Inc., A Wiley Company