Studies on the Cause of a Hemorrhagic Syndrome in Rats Fed a Water-soluble Chemically Defined Diet

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Abstract
A hemorrhagic syndrome was observed in male CDF rats fed chemically defined liquid diets containing 2.1 mg/liter menadione. The syndrome occurred without resorting to surgery, coprophagy prevention, chemotherapeutic agents or antibiotics. It was observed in CDF rats only, although rats of CFE and Fischer strains were also tested. Ethyl cysteinate·HCl, a water-soluble form of cysteine was found to be the causative factor. The incidence and severity of the syndrome were related to its concentration in the diet. The underlying mechanism was found to be the interaction of the free thiol groups of ethyl cysteinate·HCl with menadione resulting in vitamin K deficiency. Substitution of equimolar amounts of diethyl cystinate·2HCl for ethyl cysteinate·HCl or menadiol sodium diphosphate for menadione, prevented the condition. Addition of 2-methyl, 3-cysteinyl, 1,4-naphthoquinone to the diets of susceptible and resistant rat strains, suggested that it is an inactive form of menadione rather than an antimetabolite. The severity of hemorrhagenicity was increased slightly by the addition of an oxygenated fat mix to the diet, and markedly by the simultaneous supplementation of vitamins C and E. When equivalent quantities of each vitamin were added alone they were ineffective. Exclusion of vitamin A from the diet did not influence the results.