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Relationships between activities of delta-aminolevulinate synthase and heme oxygenase, respectively the rate-limiting enzymes of heme biosynthesis and degradation, have been studied in chick embryo liver cell cultures following exposure of the cultures to glutethimide and iron, a combination known to produce a synergistic induction of both enzymes. In time-course experiments, synergistic induction of heme oxygenase activity by glutethimide and iron preceded that of delta-aminolevulinate synthase by 4 h. Effects of selective inhibitors of both heme synthesis and degradation have also been studied with respect to effects on delta-aminolevulinate synthase and heme oxygenase activities. The synergistic induction of heme oxygenase by glutethimide and iron appears to be dependent upon cellular heme synthesis because addition of inhibitors of heme biosynthesis, 4,6-dioxoheptanoic acid or N-methyl-mesoporphyrin abolishes this synergistic induction. Exposure of cultures to tin-mesoporphyrin, a potent inhibitor of heme oxygenase, prevented the synergistic induction of delta-aminolevulinate synthase produced by glutethimide and iron, or, when added after induction was already established, promptly halted any further induction. These results suggest that the level of activity of heme oxygenase can reciprocally modulate intracellular heme levels and thus activity of delta-aminolevulinate synthase.

Guinea pigs fed a normal diet show the expected diurnal variation in 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Vitamin C deficiency, however, suppresses the diurnal peak activity of reductase, due to a decrease in active (unphosphorylated) enzyme. Inhibition of reductase is paralleled by both a fall in hepatic cholesterol synthesis and a rise in serum cholesterol. Incubation of normal guinea pig hepatic microsomes with physiologic and supraphysiologic concentrations of sodium ascorbate also leads to a concentration-dependent inhibition of reductase activity. Thus, dietary extremes of vitamin C may exert similar effects on reductase activity and cholesterolgenesis. Moreover, the changes in enzyme activity induced by ascorbic acid appear to be due in part to a direct effect of the vitamin on the microsomally bound enzyme.