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The water-soluble extract of Ganoderma lucidum mycelia (WER) is prepared from a solid medium composed of bagasse and rice bran overgrown with Ganoderma lucidum mycelia. Recently, we reported that WER shows a blood glucose-lowering effect in maltose-loaded non-diabetic mice. Here, we investigated the efficacy of WER in type 2 diabetic state using KK-A y mice. Moreover, the food-drug interactions of WER with α-glucosidase inhibitors, voglibose or acarbose were examined using both in vitro and in vivo experiments. Methods: The glucose-lowering effects of oral administration in vivo of WER alone, or concomitant administration of WER with voglibose/acarbose on the elevation of blood glucose levels by sugar-tolerance tests were examined in KK-A y mice. The inhibitory effects on α-glucosidase in vitro were also evaluated. Results: Oral administration of WER (1 g/kg), which did not affect fasting blood glucose, significantly suppressed the hyperglycemia after loading of maltose (18% of decrease in AUC) compared to the water-administrated control mice. In vitro study showed that WER inhibited maltase in concentration-dependent manner. The inhibitory effects of lower concentrations of voglibose or acarbose on α-glucosidase activity were additively enhanced by the presence of WER, but those of higher concentrations were not affected. The glucose-lowering effect of voglibose (0.1 mg/kg) disappeared in maltose-loaded KK-A y mice when the drug was concomitantly administrated with WER (1 g/kg), whereas acarbose (16 mg/kg) with WER showed no significant change in its effect. Conclusion: These results demonstrated that WER shows the glucose-lowering effect in maltose-loaded KK-A y , which may be based on inhibition of the α-glucosidase activity. The present study suggests that concomitant intake of WER with voglibose may override the therapeutic effect of voglibose on postprandial hyperglycemia by food-drug interaction in diabetic state.

The cytochrome P-450 3A (CYP3A) enzyme family is responsible for most of the drug metabolism in the human liver. In this study, we demonstrated the inductive effects of phenobarbital, rifampicin, carbamazepine, phenytoin, prednisolone, ciclosporin and clotrimazole on CYP3A4, CYP3A5 and CYP3A7 mRNA expression, and established the relationship between the expression of human glucocorticoid receptor alpha (hGR) mRNA and the induction of CYP3A4 mRNA in cultured HepG2 cells by reverse transcription polymerase chain reaction (RT-PCR). Treatment with prednisolone, rifampicin and carbamazepine rapidly induced the level of CYP3A4 mRNA expression by 3- to 6-fold. However, phenytoin and phenobarbital gradually induced CYP3A4 mRNA level by 3 to 4-fold. The induction of CYP3A4 mRNA expression by clotrimazole and ciclosporin was negligible. Treatment with phenytoin, rifampicin, carbamazepine and ciclosporin induced approximately 2-fold increases in the expression of CYP3A5 mRNA, although prednisolone, phenytoin and clotrimazole had no effect. Treatment with rifampicin, phenytoin, clotrimazole and ciclosporin resulted in approximately a 2-fold induction of the CYP3A7 mRNA level. Treatment with rifampicin and ciclosporin induced the expression of hGRalpha mRNA significantly in comparison with controls, although the induction of hGRalpha mRNA following treatment with other drugs was negligible. In cluster analysis, the induced level of CYP3A4, CYP3A5, CYP3A7 and hGRalpha mRNA by these drugs could be classified into four major clusters. This suggested that each cluster might be associated with different mechanism(s) of induction by these drugs. Furthermore, we studied the associations between the expression of hGRalpha mRNA and the induced level of CYP3A4 mRNA by prednisolone and ciclosporin. Treatment with both prednisolone and ciclosporin showed synergistic effects on induction of CYP3A4 mRNA and, following treatment with both drugs, the expression level of CYP3A4 mRNA was 2-fold greater compared with prednisolone alone after the fifth day. Positive correlations were observed between the levels of hGRalpha mRNA expression and those of CYP3A4 mRNA. This observation shows that the regulation of CYP3A4 gene expression was hGRalpha-dependent and that ciclosporin may function as a regulator of expression via hGRalpha.

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