Toyoko Hiroi

We investigated the expressional regulation of cytochrome P450 (CYP) 2D isoforms in rat brain by toluene. Toluene (10 mmol/kg) was injected intraperitoneally into male rats daily for 3 days. CYP2D4 level in the brain was determined by Western blotting. The level of CYP2D4 in the brain and the catalytic activity specific for this isoform were significantly increased by toluene administration. The expressions of CYP2D mRNAs in the brain were quantified by real time PCR. The mRNA level of CYP2D4 increased similar to the expression of the protein and enzymatic activity. These results showed that CYP2D4 was transcriptionally induced by toluene administration for 3 days. This is the first report that subacute exposure to toluene activated the expression of CYP2D4 mRNA in the brain. The response of CYP2D4 expression to toluene is thought to relates to the regulation of the physiological and pharmacological functions of CYP2D isoforms in the brain.

The blood glucose lowering effects in KK-Ay mice with type 2 diabetes mellitus (DM) receiving daily an intraperitoneal (i.p.) administration of Zn(II) complexes with maltol, L-threonine, and picolinic acid for 14 days were estimated under the same conditions, and dose-dependent blood glucose lowering effects in the dose range of 0.2-3.0 mg Zn/kg body weight were found. Among them, the bis(maltolato)Zn(II) complex exhibited the highest blood sugar lowering effect at the dose of 3.0 mg Zn/kg. The improvement of DM was confirmed with oral glucose tolerance tests as well as blood HbA1c levels after the administration of the three Zn(II) complexes at the dose of 3.0 mg Zn/kg. For the purpose of the clinical trial of the complexes in the future, we examined the toxic effects of these three Zn(II) complexes in regard of the LD50 values and hepatic cytochrome P450 levels. The LD50 values of the three Zn(II) complexes exhibited high values compared with that of ZnCl2. No changes of both CYP1A1 and CYP2E1 levels in the liver of KK-Ay mice treated with the three Zn(II) complexes were observed. The obtained results will be important when the complexes are tried for clinical use.