Abnormal Increase in the Expression Level of Proliferating Cell Nuclear Antigen (PCNA) in the Liver and Hepatic Injury in Rats with Dietary Cobalamin Deficiency

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Dietary cobalamin (Cbl; vitamin B_<12>) deficiency resulted in severe growth retardation in rats, and body weight in the Cbl-deficient rats at 20wk of age was significantly lower compared with the age-matched Cbl-sufficient control rats. In contrast, liver weight, when normalized to body weight, was greater in the Cbl-deficient rats than in the controls (p<0.05). The expression level of proliferating cell nuclear antigen (PCNA), a marker for cell proliferation, in the liver was significantly enhanced in the deficient rats, suggesting that cell proliferation is abnormally activated in the liver under Cbl-deficient conditions. In addition, plasma alanine aminotransferase (ALT) activity, a marker for hepatic injury, was also significantly elevated in the deficient rats. When L-carnitine, which is used clinically for the treatment of Cbl-deficient patients with methylmalonic aciduria, was administered to the Cbl-deficient rats by intraperitoneal injection twice per day for 2wk (each 0.5mmol), the amount of methylmalonic acid excreted into the urine was significantly reduced, and the plasma ALT activity was lowered to a normal level. However, the PCNA expression in the liver was barely influenced by the treatment with carnitine. In contrast, when the deficient rats were fed an L-methionine-supplemented diet (4g of L-methio-nine per kg of the diet) for 2wk, the increased expression of PCNA was normalized.
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