Sachiko Nakaya

IMPAIRED TESTICULAR FUNCTION IN RATS WITH DIET-INDUCED HYPERCHOLESTEROLEMIA AND/OR STREPTOZOTOCIN-INDUCED DIABETES MELLITUS

Hypercholesterolemia and diabetes mellitus are known to be accompanied by reproductive dysfunction. In this study, we investigated the effects of hypercholesterolemia, hyperglycemia, and these conditions combined, on testosterone (T) and testicular luteinizing hormone/human chorionic gonadotropin (LH/hCG) binding. Sprague-Dawley rats (8 weeks old) were divided into four groups: Group 1 was the control, group 2 was fed standard chow containing 2% cholesterol (C-diet), group 3 was administered streptozotocin (STZ, 65 mg/kg, i.p.), group 4 was treated with both the C-diet and STZ. After 4 weeks, rats were sacrificed. Serum glucose was significantly higher in the STZ group (304% that of controls) and the C-diet plus STZ group (345%), but there was no difference between the C-diet group (89%) and the control group. Serum cholesterol was significantly higher in the C-diet group (206% that of controls), the STZ group (452%) and the C-diet plus STZ group (2042%). Serum T, testicular T, and LH/hCG binding were significantly lower in the C-diet group (49%, 52%, and 81% that of controls, respectively), the STZ group (15%, 32%, and 72%) and the C-diet plus STZ group (8%, 21%, and 57%). These results suggest that hypercholesterolemia is an independent risk factor for testicular dysfunction and that the reduction of serum and testicular T levels is due at least in part to a reduction in testicular LH/hCG binding in rats with hypercholesterolemia, hyperglycemia, and these conditions combined. It is further suggested that the reduction in LH/hCG binding is mainly related to a rise in serum cholesterol levels.

Effects of Estrogen on Serum Leptin Levels and Leptin mRNA Expression in Adipose Tissue in Rats

Objective: In this study, we examined changes in serum leptin levels during the estrus cycle and the role of estrogen in these changes. Methods: We measured serum leptin levels during normal estrus cycles in intact rats and estradiol-17β (E2)-induced artificial estrus cycles in ovariectomized rats. Results: Serum leptin levels increased 1.6-fold from 4.2 ± 0.2 ng/ml during diestrus stage 2 to 6.7 ± 0.9 ng/ml during proestrus stage during the 4-day estrus cycle. During the E2-induced estrus cycle, serum leptin levels increased 2.3-fold from 2.3 ± 0.1 ng/ml at estrus to 5.4 ± 1.2 ng/ml at proestrus. E2 also increased serum leptin concentrations and leptin mRNA expression in adipose tissue of immature rats. Discussion: These findings suggest that increased serum leptin induced by estrogen during proestrus may trigger the preovulatory release of luteinizing hormone. Furthermore, our findings indicate that estrogen has a positive effect on leptin production in adipose tissue.

Ursodeoxycholic acid prevents hepatic cytochrome P450 isozyme reduction in rats with deoxycholic acid-induced liver injury.

BACKGROUND/AIMS Hydrophobic bile acids, such as deoxycholic acid produce cholestatic liver injury. Ursodeoxycholic acid has been shown to be useful in the treatment of cholestatic liver disease. METHODS In this study, we investigated the effects of deoxycholic acid or ursodeoxycholic acid (1% of diet, for 14 days) and their combination (1% each) on expression of hepatic cytochrome P450 isozymes, their related enzyme activities and mRNA level in rats. RESULTS Adding 1% deoxycholic acid to chow caused a marked increase in serum total bilirubin (47-fold) and total bile acid (8-fold) concentrations and in alkaline phosphatase (2.5-fold, p<0.01) and alanine aminotransferase activities (23.5-fold, p<0.01). Adding the same dose of ursodeoxycholic acid along with the deoxycholic acid mitigated both the rise in serum total bilirubin and bile acid concentrations and that in alkaline phosphatase and alanine aminotransferase activities, although the use of ursodeoxycholic acid alone did not affect any of the above. Feeding 1% deoxycholic acid caused a decrease (48% of control) in total cytochrome P450 content in hepatic microsomes. Addition of 1% ursodeoxycholic acid along with the 1% deoxycholic acid completely prevented the decrease in total cytochrome P450 content. Feeding ursodeoxycholic acid alone did not affect the total cytochrome P450 content. The expression of cytochrome P450 2B1, 2E1, 3A2, 2C6, 2C11 and 4A1 proteins in hepatic microsomes was decreased by deoxycholic acid (44, 51, 23, 59, 30 and 74% of control, respectively). Likewise, the activities of cytochrome P450 2B1 (pentoxyresorufin O-depentylation), 2E1 (aniline p-hydroxylation) and 3A2 (testosterone 6beta-hydroxylation) isozymes and the 3A2 mRNA levels in liver were decreased by deoxycholic acid. Addition of 1% ursodeoxycholic acid to 1% deoxycholic acid also prevented the decrease in these cytochrome P450 proteins, related enzyme activities and mRNA levels in liver. CONCLUSIONS These results indicate that, in rats with deoxycholic acid-induced liver injury, ursodeoxycholic acid prevents the decrease in hepatic cytochrome P450 isozymes and suggest that ursodeoxycholic acid is useful for the treatment of liver injury in terms of aiding the normalization of the hepatic drug-metabolizing system.

Relationship between efficacy of risperidone and genetic polymorphism in schizophrenia treatment

We investigated the relationship between the genetic polymorphism of the dopamine 2 receptor Taq1A in patients receiving risperidone treatment and the efficacy of drug treatment. The subjects were 19 patients with schizophrenia from whom we obtained informed consent. Their clinical symptoms were evaluated using the Positive and Negative Syndrome Scale for Schizophrenia (PANSS), and extrapyramidal symptoms (EPS) were evaluated using the Drug-induced Extrapyramidal Symptoms Scale (DIEPSS). Genomic DNA was extracted from peripheral blood using a kit and the polymorphism of the dopamine 2 receptor Taq1A was identified by the polymerase chain reaction–restriction fragment length polymorphism method. The following results were obtained before and after risperidone treatment. General psychopathological scale score in PANSS: the A2/A2 group showed higher scores than the A1/A2 group. Total DIEPSS score: the A2/A2 group showed lower scores than the A1/A1 group. From these results the following can be concluded. Risperidone treatment tended to improve symptoms in the A2/A2 group compared with the A1/A2 group; however, no significant difference in improvement was observed between the A2/A2 group and the A1/A1 group, indicating no definitive tendency that genetic polymorphism affects risperidone treatment outcome. On the other hand, there is the possibility that the TaqA2 allele induces the expression of EPS.