Application to Butterbur Products of a Suggested Daily Intake-Based Safety Evaluation of Individual Herbal Supplements with Cytochrome P450 Expression as a Major Index.

The present paper first proposes a method for ensuring the safety of commercial herbal supplements, termed the suggested daily intake-based safety evaluation (SDI-based safety evaluation). This new method was inspired as a backward analog of the acceptable daily intake (ADI) derivation from the no observed adverse effect level (NOAEL), the basis of food additive risk analysis; namely, rats are dosed with individual herbal supplement products at the SDI for human use multiplied by 100 (the usual uncertainty factor value) per body weight for 8 d. The primary endpoint is the sign of adverse effects on liver, especially gene expression of cytochrome P450 (CYP) isoforms. The proposed method was then applied to three butterbur (Petasites hybridus) products without pyrrolizidine alkaloids but lacking clear safety information. Results showed that two oily products markedly enhanced the mRNA expression of CYP2B (>10-fold) and moderately enhanced that of CYP3A1 (<4-fold) with liver enlargement. These products also caused the renal accumulation of alpha 2-microglobulin. One powdery product showed no significant effect on liver and kidney. The large difference in effects of products was due to the difference in chemical composition revealed by liquid chromatography-mass spectroscopy. The oily and the powdery products required attention in terms of safety and effectiveness, respectively. Finally, the results from the SDI-based safety evaluation of butterbur and other herbal supplement products were grouped into four categories and cautionary notes were discussed. The SDI-based safety evaluation of their products by herbal supplement operators would contribute to safe and secure use by consumers.

[Exploratory Study of the Risk Factors for Acute Kidney Injury in the Cisplatin Combination Chemotherapy for Solid Cancer].

In the present study, we investigated the rate of cisplatin(CDDP)-induced acute kidney injury(CIA)and examined its association with various clinical factors in the combination therapy with CDDP for solid cancers. A total of 726 cases of solid cancer that had been indicated for the CDDP combination regimen from December 2012 to December 2013 were enrolled. CIA occurred in 48 cases(6.6%). The multivariate analysis revealed that diabetes, the regular use of non-steroidal anti- inflammatory drugs(NSAIDs), first dose of CDDP, and severe hyponatremia(≥Grade 3)within one week after CDDP administration were significantly associated with an increased risk for CIA, whereas magnesium supplementation was associated with a significantly reduced risk for CIA. Particularly, diabetes and cardiovascular disease were identified as risk factors for CIA in patients with esophageal and head and neck cancers. Based on the results of this survey, it is important to formulate preventive measures, evaluate risk factors, and respond rapidly.

Down-regulation of alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase by polyunsaturated fatty acids in hepatocytes is not mediated by PPARalpha.

BACKGROUND: alpha-Amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD) is a key enzyme in NAD biosynthesis from tryptophan. Dietary polyunsaturated fatty acids (PUFA) have been shown to suppress hepatic ACMSD activity and its mRNA level in rat. However the mechanism of the suppressive action has not been clarified yet. Although the phenomena that fatty acids suppress the expression of ACMSD in rat liver have been established in vivo experiment, it is still obscure whether the effect of fatty acids on the expression of the enzyme is caused by its direct or indirect action, because there have been very few investigations performed in vitro. AIM OF THE STUDY: In this study, to examine whether down-regulation of ACMSD mRNA by PUFA involves peroxisome proliferator-activated receptor (PPAR) alpha mediated mechanism or not, we investigated the effect of PUFA on the ACMSD expression by using primary cultured rat hepatocytes. METHODS: For this purpose we investigated the effect of PUFA (linoleic acid and eicosapentanoic acid) on the ACMSD mRNA level in primary-cultured rat hepatocytes and compared its effect with that of WY-14,643 (a PPARalpha agonist). After the incubation of hepatocytes with fatty acids, WY-14,643 and/or MK886 (a PPARalpha antagonist), mRNA levels of ACMSD and a peroxisome marker enzyme acyl-CoA oxidase (ACO) were determined by competitive reverse transcription-polymerase chain reaction (RT-PCR) method. RESULTS: ACMSD mRNA level in primary hepatocytes were decreased by the incubation with high concentrations of linoleic acid, eicosapentaenoic acid (EPA) and WY-14,643. The appearance of ACO mRNA by WY-14,643 was remarkably increased, and those by linoleic acid and EPA were increased less than that by WY-14,643. Moreover, the suppression of ACMSD mRNA and the augmentation of ACO mRNA by WY-14,643 were inhibited by MK886, but the suppression by PUFA was not substantially affected by MK886. CONCLUSIONS: The present study suggesting that the mechanism of decrease in ACMSD mRNA level by PUFA was different from that by WY-14,643, and that there would be any pathway other than PPARalpha mediated one for PUFA to regulate ACMSD expression.