Metabolomic Analysis of Complex Chinese Remedies: Examples of Induced Nephrotoxicity in the Mouse from a Series of Remedies Containing Aristolochic Acid

Abstract

Aristolochic acid nephropathy is caused by aristolochic acid (AA) and AA-containing herbs. In traditional Chinese medicine, a principle called “Jun-Chen-Zou-Shi” may be utilized to construct a remedial herbal formula that attempts to mitigate the toxicity of the main ingredient. This study used Bu-Fei-A-Jiao-Tang (BFAJT) to test if the compound remedy based on a principle of “Jun-Chen-Zou-Shi” can decrease the toxicity of AA-containing herbs. We compared the three toxicities of AA standard, Madouling (an Aristolochia herb), and a herbal formula BFAJT. AA standard was given for BALB/c mice at a dose of 5 mg/kg bw/day or 7.5 mg/kg bw/day for 10 days. Madouling and BFAJT were given at an equivalence of AA 0.5 mg/kg bw/day for 21 days. Nephrotoxicity was evaluated by metabolomics and histopathology. The urinary metabolomics profiles were characterized by 1H NMR spectroscopy. The spectral data was analyzed with partial least squares discriminant analysis, and the significant differential metabolites between groups were identified. The result showed different degrees of acute renal tubular injuries, and metabolomics analysis found that the kidney injuries were focused in proximal renal tubules. Both metabolomics and pathological studies revealed that AA standard, Madouling, and BFAJT were all nephrotoxicants. The compositions of the compound remedy did not diminish the nephrotoxicity caused by AA.

Differential microRNA expression in aristolochic acid-induced upper urothelial tract cancers ex vivo

“…In traditional Chinese medicine, a phenomenon termed the 'Jun-Chen-Zou-Shi' principle entails constructing a remedial herbal formula to mitigate the toxicity of the main ingredient. Recently Tsai et al ( 52 ) performed metabolic analysis using 1 H-NMR spectroscopy to validate whether Bu-Fei-A-Jiao-Tang, a compound remedy based on this principle, could decrease the toxicity of AA-containing herbs; however, the result did not support this claim. Thus, the function of the Jun-Chen-Zou-Shi principle was not able to ensure a reduction in AA nephrotoxicity.…”

Vitamin C attenuates the toxic effect of aristolochic acid on renal tubular cells via decreasing oxidative stress-mediated cell death pathways

“…Because AA is a component of various Traditional Chinese Medicinal plants (7,(52)(53)(54)(55)(56), it is important to discover means of preventing AA-induced renal damage. Though studies have developed a monoclonal antibody against AA-induced cytotoxicity (3,57,58), most approaches are directed against oxidative stress to suppress AA-induced cytotoxicity.…”

“…Numerous studies have demonstrated that AA can cause nephropathy (4)(5)(6). In traditional Chinese medicine, asarum and aristolochia are usual components of complex Chinese remedies applied to treat arthritic pain, cough and gastrointestinal symptoms (7)(8)(9). Therefore, AA-induced nephropathy is widely discussed in China (10,11).…”

Metabolomics in Nephrotoxicity

“…A combined GC-MS and LC-MS metabolic profiling was designed to evaluate AA nephrotoxicity. Nephrotoxicity was dose-dependent during onset, development, and partial recovery [59,60]. A subsequent study showed that homocysteine formation and the folate cycle were significantly increased, but metabolic pathways of AA biosynthesis were decreased in these rats [53].…”