Corynebacterium parvum: Effects on the Biochemistry of Mouse Serum and Liver2

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Abstract
The ip injection of 400 µg of ZnCI2 abrogated the lethality of 800 µg of Escherlchla coll endotoxin injected ip, but not iv, into normal noninbred CD®-1 Swiss mice (median lethal dose =450 µg endotoxin). Corynebacterium parvum-treated mice (1.0 mg/mouse) became hypersensitive to both iv and ip endotoxln, and 25 µg was lethal. ZnCI2 given ip at 400 µg to C. par-vum-treated mice did not prevent endotoxin (ip or iv) lethality nor did it inhibit the release of tumor necrosis factor into the circulation. Accordingly, a search was made for alterations in the liver metabolism of trace metals, carbohydrates, and toxins that might be related to the development of endotoxin hyperreactivity in C. parvum-treated mice. An iv injection of 25 µg endotoxin into normal mice (serum zinc = 108 µg/dl ) caused serum zinc to fall to 68 µg/dl after 2 hours and to 33 µg/dl after 6 hours. Serum zinc was 79 µg/dl 2 hours after administration of 25 µg endotoxin iv in mice treated with C. parvum 4 days earlier. Mice treated with C. parvum 8 or more days earlier did not show a serum zinc response to a challenge with endotoxin. Immunologicaily inactive C. parvum (strain CN-5888), which does not induce hyperspleno-megaly or hyperreactivity to endotoxin, did not result in the loss of the serum zinc response to endotoxin. Glycogen in the livers of untreated and C. parvum-treated mice was 37.4 and 19.9 mg/g, respectively. Endotoxin (25 µg) did not cause a significant change in the amount of liver glycogen in normal mice but did result in a decrease in the amount of liver glycogen in C. par-vum-treatrd mice from 19.9 to 9.9 mg/g. Microsomes from C. parvum-treated mouse livers had significantly decreased cyto-chrome P450, aminopyrine demethylase, and lipid peroxidase. In the pyrldine nucleotide-metabolizing system, the total pyridine nucleotlde concentration in livers from C. parvum-treated mice was 50% of the normal level. The sharply lowered concentration of NADPH accounted for essentially all of this decrease. Glucose 6-phosphate dehydrogenase (Glc-6-PD), the enzyme that regenerates NADPH from NADP, was increased by 1,500% in livers from C. parvum-treated mice. The extent of the increase in Glc-6-PD activity strictly depended on the stock of mice and on the strain of C. parvum used as the reticuloendotheiial stimulating agent. The results of these studies, itemizing some of the metabolic changes that occur following immunostimulation with C. parvum and identifying a strong dependence on mouse stock, suggest that the response to C. parvum may vary considerably in different species of animals with significant metabolic consequences.