Effects of Ninjin'yoeito on Human CYP3A and Mouse CYP3A Activity.

Ninjin'yoeito (NYT) is widely used clinically for the management of patients with frailty and other multiple symptoms. NYT is often administered with other drugs; however, little information is available on its drug interactions. Previous studies using human liver microsomes have reported that constituents of NYT either inhibit (schisandra fruit, cinnamon bark, glycyrrhiza, and poria sclerotium) or induce (schisandra fruit and glycyrrhiza) CYP3A4 expression. Herein, we conducted in vitro and in vivo studies targeting human CYP3A and mouse CYP3A to elucidate the effects of NYT coadministration with other drugs on hepatic drug metabolism. In an inhibition study using human liver microsomes, NYT showed concentration-dependent reversible inhibition and time-dependent inhibition. Furthermore, in an induction study using frozen human hepatocytes, the addition of 0.01-0.1 mg/mL NYT resulted in a concentration-dependent increase in CYP3A gene expression. Contrarily, no significant changes in CYP3A substrate blood concentrations were observed between untreated mice and mice that received either a single dose of NYT or repeated doses for 15 days. These results demonstrate that NYT has inhibitory and inductive effects on hepatic CYP3A in vitro, but orally administered NYT does not affect drug metabolism mediated by hepatic CYP3A in vivo in the mouse model. Although there is a little information about drug interactions of NYT, this study provides new evidence for that.

Saireito Improves Lymphatic Function and Prevents UVB-Induced Acute Inflammation and Photodamage in HR-1 Hairless Mice.

A single high-dose ultraviolet B (UVB) exposure on the skin induces acute inflammatory responses, such as an increase in proinflammatory cytokines (e.g., IL-6 and IL-1ß), hyperpermeability and dilation of blood and lymphatic vessels, and infiltration of inflammatory cells. These responses result in different cutaneous disorders characterized by erythema, epidermal hyperplasia, edema formation, and extracellular matrix degradation. Saireito extract (SRT), a traditional Chinese medicine, has been used to treat various inflammatory diseases in Japan, and SRT and its major active components (e.g., saikosaponins and baicalin) were reported to downregulate proinflammatory cytokines. Moreover, SRT has a protective effect against UV irradiation in vitro. Based on these findings, we aimed to investigate the effect of SRT on UVB-induced photodamage and structural change in the vasculature. We pretreated male HR-1 hairless mice with SRT (625 or 1250 mg/kg) for 3 weeks before a single UVB (250 mJ/cm2) irradiation. SRT treatment attenuated UVB-induced increases in erythema, transepidermal water loss, and edema formation at 72 h after irradiation. SRT treatment also suppressed UVB-induced inflammatory cell infiltration and collagen degradation. Furthermore, at 24 h after irradiation, SRT treatment inhibited UVB-induced upregulation of proinflammatory cytokines and reduction in lymphatic vessel density associated with upregulation of VEGF-C expression. These results suggest that SRT could attenuate UVB-induced photodamage. This protective effect of SRT involves suppression of upregulation of proinflammatory cytokines and improvement of lymphatic function in the early stage of inflammation.

Oral administration of Jumihaidokuto inhibits UVB-induced skin damage and prostaglandin E2 production in HR-1 hairless mice.

This study was conducted to investigate whether and how Jumihaidokuto (JHT), a traditional Chinese medicine, prevents UVB-induced skin damage in male HR-1 hairless mice. JHT has been traditionally prescribed for patients presenting skin disorders with redness and swelling, and, in Japan, it is approved for prescription to patients with acute and/or purulent skin disorders, hives, acute eczema, and athlete's foot. Considering the traditional use of JHT, we hypothesized that oral administration of JHT might emerge as an effective strategy to prevent UVB-induced skin damage, such as edema and erythema. Here, we pretreated mice with JHT (1000 mg/kg, p.o.) for 3 weeks and then administered a single dose of UVB irradiation (250 mJ/cm2) on the dorsal skin. UVB irradiation increased the erythema index and transepidermal water loss (TEWL) and decreased the skin water content in the epidermis at 72 h post-irradiation. JHT treatment inhibited the increase of TEWL and the loss of water content in the epidermis, but not the elevation of the erythema index. Moreover, administration of JHT suppressed UVB-induced epidermal hyperplasia by blocking the proliferation of keratinocytes and also inhibited irradiation-triggered reduction of collagen fibers and infiltration of immune cells into the dermis. Lastly, administration of JHT suppressed UVB-induced production of proinflammatory mediators, such as prostaglandin E2 and interleukin-1ß. These results suggest that JHT prevents UVB-induced skin damage and that the underlying mechanism involves the inhibition of proinflammatory mediators.

Simultaneous collection of the portal and superior vena cava blood in conscious rats defined that intestinal epithelium is the major site of glucuronidation, but not sulfation and methylation, of quercetin.

Quercetin is a flavonoid with many physiological effects. Absorbed quercetin is rapidly conjugated in the intestinal epithelium and liver. Different positional isomers of quercetin conjugates have different physiological properties. However, the mechanisms of quercetin conjugation in the intestine are not fully clarified. We examined the regioselective quercetin conjugate formation in the intestine after oral administration of quercetin glycosides, by simultaneous sampling of blood from the portal vein and superior vena cava, and quantifying various positional isomers of quercetin glucuronides and sulfates in conscious rats. Concentrations of quercetin glucuronides were higher in blood from the portal vein than the superior vena cava, showing that glucuronidation mainly occurred in the intestine. Such differences were not observed for quercetin sulfates. Regioselectivity of the intestinal glucuronidation in quercetin hydroxyl groups were 7- >3'- >3- >4'-OH. Quercetin was mainly sulfated on 3'-OH at 30 min, but on 4'-OH at 240 min.

Protodioscin, Isolated from the Rhizome of Dioscorea tokoro Collected in Northern Japan is the Major Antiproliferative Compound to HL-60 Leukemic Cells.

BACKGROUND: The rhizome of Oni-dokoro (a wild yam, Dioscorea tokoro) has extremely bitter taste and is not generally regarded edible;, however, in northern part of Japan, such as Iwate and a part of Aomori, it is used as health promoting food. To clarify the reason, we examined the biologically active compounds in the rhizome collected at Iwate and compared them from the other area in literature. METHODS: The acetonitrile extract from northern part of Japan was purified by bioassay-guided separation using antiproliferative activity to human leukemia HL-60 cell, and protodioscin (PD) was isolated and identified by instrumental analyses as the major active compound. RESULTS: PD known as a saponin with four sugar moieties, an inhibitor for platelet aggregation, and a low density lipoprotein (LPL) lowering agent, displayed strong growth inhibitory effect to HL-60. The literature search suggested that the rhizome from other area contained dioscin and other saponins with three sugar moieties as their major component. We assume that the edible and health promoting effect of the rhizome in the particular area is partially derived from these different components. CONCLUSION: We were interested in the differences of utilization in the rhizome of wild yam Dioscorea tokoro, and examined the chemical composition in the rhizome to find protodioscin as antiproliferative compound to HL-60. In the report from other area, the rhizome exhibited dioscin as the major compound. Our study indicated that the protodioscin/dioscin composition varied regionally, although the reason is still needs to be investigated.