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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.

In this study, we report that expression of the 𝘢𝘳𝘨𝘊𝘉𝘏 operon is induced in stationary phase cultures and that this increase is largely dependent on RpoS, the alternative stress sigma factor. Using combinatorial 𝘢𝘳𝘨𝘙 and 𝘳𝘱𝘰𝘚 mutants, we evaluated the relative contributions of these two regulators to the expression of 𝘢𝘳𝘨𝘏 using operon 𝘭𝘢𝘤𝘡 fusions. While ArgR was found to be the main factor responsible for de-repression of the 𝘢𝘳𝘨𝘊𝘉𝘏 operon, RpoS was required for full expression of this biosynthetic operon at concentrations below 10 μg arginine ml⁻¹, a level at which growth of an arginine auxotroph was arginine limited. At high arginine concentrations (>10 μg ml⁻¹) 𝘢𝘳𝘨𝘊𝘉𝘏 expression was strongly repressed as expected by ArgR. 𝘢𝘳𝘨𝘊𝘉𝘏 expression was 30 fold higher in Δ𝘢𝘳𝘨𝘙 mutants relative to a wild type fully repressed strain and this expression was independent of RpoS. These results indicate that RpoS plays an important role in the regulation of arginine biosynthesis, particularly when the operon is partially de-repressed as would be the case in starvation conditions. / Thesis / Master of Science (MS)

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