The Journal of Korean Medicine (대한한의학회지)

The Society of Korean Medicine (대한한의학회)
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Sub-acute toxicity and effect of Hwangryunhaedok-tang on human drug-metabolizing enzymes

  • Jin, Seong Eun (K-herb Research Center, Korea Institute of Oriental Medicine) ;
  • Lee, Mee-Young (K-herb Research Center, Korea Institute of Oriental Medicine) ;
  • Seo, Chang-Seob (K-herb Research Center, Korea Institute of Oriental Medicine) ;
  • Shin, Hyeun-Kyoo (K-herb Research Center, Korea Institute of Oriental Medicine) ;
  • Cho, Jae-Woo (Pathology Research Center, Korea Institute of Toxicology) ;
  • Ha, Hyekyung (K-herb Research Center, Korea Institute of Oriental Medicine)
  • Received : 2017.04.06
  • Accepted : 2017.05.29
  • Published : 2017.06.30
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Abstract

Objectives: Hwangryunhaedok-tang (HHT; Huanglianjiedu-tang, Orengedoku-to), a traditional herbal formula, is used for treating inflammation, hypertension, gastritis, liver dysfunction, cerebrovascular diseases, dermatitis and dementia. The objective of this study was to assess the sub-acute toxicity of HHT in Sprague-Dawley (SD) rats, and its effect on the activities of human microsomal cytochrome P450s (CYP450s) and UDP-glucuronosyltransferases (UGTs). Methods: Male and female SD rats were orally administered HHT once daily at doses of 0, 500, 1000 and 2000 mg/kg for 4 weeks. We analyzed mortality, clinical observations, body weight, food consumption, organ weights, urinalysis, hematology, serum biochemistry, and histopathology. The activities of major human CYP450s (CYP1A2, CYP3A4, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP2E1) and UGTs (UGT1A1, UGT1A4, and UGT2B7) were assessed using in vitro fluorescence- and luminescence-based enzyme assays, respectively. Results: No toxicologically significant changes related to the repeated administration of HHT were observed in both male and female SD rats. The no observed adverse effect level (NOAEL) value was more than 2000 mg/kg/day for both sexes. HHT inhibited the activities of human microsomal CYP1A2, CYP2C19, CYP2D6, and CYP2E1, whereas it weakly inhibited the activities of CYP2B6, CYP2C9, CYP3A4, and UGT1A1. In addition, HHT negligibly inhibited the activities of human microsomal UGT1A4 and UGT2B7 with $IC_{50}$ values in excess of $1000{\mu}g/mL$. Conclusions: Our findings indicate that HHT may be safe for repeated administration up to 4 weeks. In addition, these findings provide information on the safety and effectiveness of HHT when co-administered with conventional drugs.

Keywords

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