Chemoprevention of vinyl carbamate-induced lung tumors in strain A mice.

The ability of potential chemopreventive agents to prevent vinyl carbamate-induced lung tumors was determined in 2 different experiments. Female strain A mice administered intraperitoneally either a single injection of 60 mg/kg vinyl carbamate that induced 24.0 +/- 1.72 tumors/mouse at 24 weeks or 2 injections of 16 mg/kg vinyl carbamate each (32 mg/kg total dose) that induced 43.2 +/- 3.2 tumors/mouse at 20 weeks. Lung carcinomas were found as early as 16 weeks. Dexamethasone and piroxicam provided in the diet were found to significantly inhibit lung tumors induced by 60 mg/kg vinyl carbamate at 24 weeks whereas myo-inositol also provided in the diet, did not significantly inhibit tumor formation. In animals given 6 16-mg/kg doses of vinyl carbamate, tumor multiplicity was reduced roughly 25% by alpha-difluoromethylornithine and green tea and reduced 50% by dexamethasone and piroxicam. Combinations of these agents were also tested using a total dose of 32 mg/kg of vinyl carbamate. Although alpha-difluoromethylornithine and green tea did not result in a significant inhibition of lung tumor formation if used alone, the combination of alpha-difluoromethylornithine and green tea resulted in a significant reduction of tumor multiplicity. The combinations of alpha-difluoromethylornithine or green tea with either dexamethasone or piroxicam or the combination of dexamethasone and piroxicam did not decrease tumor multiplicity greater than achieved by dexamethasone and piroxicam alone. In summary, selected chemopreventive agents previously shown to inhibit lung tumors by other chemical carcinogens also inhibited vinyl carbamate-induced lung tumors.

Carnitine deficiency associated with ornithine transcarbamylase deficiency.

An infant with X-linked recessive ornithine transcarbamylase deficiency is described who also had severe deficiency of plasma and liver carnitine during normoammonemic periods. Treatment with L-carnitine (100 mg/kg/day) for 12 months decreased the frequency of hospitalizations for hyperammonemia, although it did not alter his neurologic status. This report demonstrates that persistent carnitine deficiency may be present in patients with ornithine transcarbamylase deficiency even when plasma ammonia is normal. Carnitine evaluation and supplementation may be important in the treatment of patients with this metabolic disorder.

Metabolic studies of carnitine in a child with propionic acidemia.

Carnitine metabolism was studied in a 7-y-old boy with propionic acidemia due to an almost total deficiency of propionyl-CoA carboxylase. The initial diagnosis was made at 3 wk of age followed by numerous episodes of metabolic acidosis despite a low-content branch-chain amino acid diet containing supplemental biotin. Although clinically stable and in a nonacidotic state, the plasma concentration of total carnitine was normal (38.9 microM; normal = 46 +/- 10, mean +/- SD, n = 30) whereas free carnitine was decreased (5.7 microM; normal = 37 +/- 8) and short-chain acylcarnitines were increased (28.6 microM; normal = 5.7 +/- 3.5). Skeletal muscle and liver specimens obtained at open biopsy had low total and free carnitine contents and increased ratio of short-chain acylcarnitines to free carnitine. Short-chain acylcarnitine content was low in liver but increased in skeletal muscle. The liver contained fatty vacuoles, enlarged mitochondria with paracrystalline inclusions, and numerous peroxisomes whereas the skeletal muscle also had lipid vacuoles and an increase in number and size of mitochondria. A carnitine challenge test (100 mg L-carnitine/kg body wt via a gastrostomy tube) resulted in a peak plasma carnitine concentration at 120 min. With maintenance therapy of 100 mg L-carnitine/kg/day the plasma free carnitine remained relatively low, the plasma glycine concentration decreased, and urinary acylcarnitine excretion increased. This study demonstrates that the alterations in carnitine and its derivatives observed in plasma and urine reflect the same type of altered distribution in tissue and provides further data on the effects of L-carnitine therapy.