Valproic acid increases biliary copper excretion in the rat
Introduction
Copper is an essential metal and is an integral cofactor for numerous enzymes, whereas copper accumulation leads to tissue damage. The regulatory mechanisms of copper concentration, including absorption, distribution, metabolism and excretion, are therefore important for protection against deficiency and accumulation. Several diseases and conditions influence copper homeostasis. Menkes' syndrome and Wilson's disease are well-known human inherited disorders caused by genetic defects in copper metabolism in which copper levels in the body were found to increase (Bull and Cox, 1994). Some diet and drugs have been shown to affect copper absorption (Cousins, 1985, Wapnir and Sia, 1996). One of these is antiepileptic drugs. Valproic acid (VPA) is widely used as a drug of the first choice in the treatment of epileptic patients with generalized and partial seizures. In patients administered VPA, abnormalities in the serum copper concentration have been reported and there is controversy over the concentration of copper in the serum of epileptic patients treated with VPA. Serum copper concentrations have been found to be decreased (Fichsel et al., 1983, Kaji et al., 1992), unchanged (Hurd et al., 1984, Verrotti et al., 2002), or increased (Kuzuya et al., 1993) in the presence of VPA.
During phenytoin treatment, a change in the blood concentration of zinc has been reported. Concerning these changes induced by antiepileptic drugs, Weismann et al. (1978) have proposed that the formation of chelate between zinc and phenytoin causes an increase in the absorption of zinc from the gastrointestinal tract in rats. The absorption of dietary copper from the gastrointestinal tract may be affected by treatment of VPA.
The biliary copper excretion is important for homeostatic regulation, because biliary excretion is quantitatively the major excretory route (Dijkstra et al., 1996). In animal experiments, VPA has an important pharmacological effect on copper homeostasis, since treatment with VPA increases bile flow (Dickinson et al., 1979, Watkins and Klaassen, 1981, Liu et al., 1992). From these points of view, changes in the excretion of copper from the hepatobiliary pathway by treatment with VPA should be also considered.
The purpose of the present study was first to determine if there were any changes in the absorption of copper from the gastrointestinal tract; and second, to assess the biliary excretion of copper with or without VPA treatment using an in situ recirculating perfusion method in rat small intestine.
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Animal procedures
All experiments were performed in accordance with the Guidelines for Animal Experiments of Nagoya University School of Medicine.
Male Wistar rats (Japan SLC Inc., Shizuoka, Japan) weighing 280–310 g were housed in suspended stainless steel cages. The animals were allowed free access to food (Nihon Clea, Tokyo, Japan) and water, although food was withheld overnight before the experiment. Under sodium pentobarbital anesthesia (25 mg/kg i.p.), rats were placed on an operating plate. Anesthesia was
Results
The time courses of the changes in perfusate volume, perfusate copper concentration and copper amount are shown in Fig. 1. There was no significant change on addition of VPA (20 mg/30 ml) in either perfusate volume (P=0.8) (Fig. 1A) or perfusate copper concentration (P=0.7) (Fig. 1B) or copper amount (P=0.7) (Fig. 1C). The absorption rate constant adjusted for intestinal length (ka) did not change significantly in the presence of VPA (Table 1). These results indicated that the abnormalities of
Discussion
In the present study, the decline in copper during the perfusion did not change in the presence of VPA, although VPA was absorbed into the systemic circulation (Fig. 1C and Table 1). Palm and Hallmans (1982) have shown that phenytoin treatment in epilepsy patients increases serum zinc and copper concentrations and they proposed that a chelate formation between the drug or its metabolites and the metal can increase the absorption of the metal in the intestine. But our results indicate that VPA
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