Aristololactam I
Aristololactam I (AL-I), the main metabolite of aristolochic acid I (AA-I), it can lead to renal damage, the cytotoxic potency of Aristololactam I is higher than that of AA-I and that the cytotoxic effects of these molecules are mediated through the induction of apoptosis in a caspase 3-dependent pathway.
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24 months(2-8C).
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Toxicol In Vitro. 2010 Jun;24(4):1092-7.
Toxicities of aristolochic acid I and aristololactam I in cultured renal epithelial cells.[Pubmed:
20338233]
Aristolochic acid nephropathy, a progressive tubulointerstitial renal disease, is primarily caused by aristolochic acid I (AA-I) intoxication. Aristololactam I (AL-I), the main metabolite of AA-I, may also participate in the processes that lead to renal damage.
METHODS AND RESULTS:
To investigate the role and mechanism of the Aristololactam I -mediated cytotoxicity, we determined and compared the cytotoxic effects of AA-I and Aristololactam I on cells of the human proximal tubular epithelial (HK-2) cell line. To this end, we treated HK-2 cells with AA-I and Aristololactam I and assessed the cytotoxicity of these agents by using the 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay, flow cytometry, and an assay to determine the activity of caspase 3. The proliferation of HK-2 cells was inhibited in a concentration- and time-dependent manner. Cell-cycle analysis revealed that the cells were arrested in the S-phase. Apoptosis was evidenced by the results of the annexin V/propidium iodide (PI) assay and the occurrence of a sub-G1 peak. In addition, AA-I and AL-I increased caspase 3-like activity in a concentration-dependent manner.
CONCLUSIONS:
These results also suggested that the cytotoxic potency of Aristololactam I is higher than that of AA-I and that the cytotoxic effects of these molecules are mediated through the induction of apoptosis in a caspase 3-dependent pathway.
Zhongguo Zhong Yao Za Zhi. 2004 Jan;29(1):78-83.
Injury in renal proximal tubular epithelial cells induced by aristololactam I.[Pubmed:
15709390]
To study whether Aristololactam I (AL-I) induces injury in human renal proximal tubular epithelial cells.
METHODS AND RESULTS:
Cultured human renal proximal tubular epithelial cell line HK-2 was used as the subject. Aristolochic Acid I (AA-I) was used as a positive control. Cell toxicity of Aristololactam I was detected by LDH releasing rate. Cell apoptosis was evaluated by cellular morphology, DNA content and expression of cell membrane phosphatidylserine (PS). The secretion level of fibronectin (FN) and TGF-beta1 in HK-2 cells were assayed by ELISA. Aristololactam I had a direct toxicity on HK-2 in a dose dependent manner from 2.5 mg x mL(-1) to 20 mg x mL(-1); In these range of concentration, Aristololactam I could induce cell apoptosis which was detectable by measurements of morphology, DNA content and expression of PS. Aristololactam I could stimulate the secretion of FN and TGF-beta1. The potency of Aristololactam I cell toxicity was higher than AA-I at the same concentration. The effects of Aristololactam I on apoptosis, secretion of FN and TGF-beta1 were all weaker than AA-I.
CONCLUSIONS:
Aristololactam I as one metabolite of AA-I in vivo induces direct injury in renal proximal tubular cells. Its effects are similar to those of AA-I. Aristololactam I may be one of toxic metabolites in Chinese herbs containing AA which participate in renal damage and fibrosis.
Beijing Da Xue Xue Bao. 2004 Feb;36(1):36-40.
Cellular mechanism of renal proximal tubular epithelial cell injury induced by aristolochic acid I and aristololactam I[Pubmed:
14970885]
To investigate the cellular mechanism of renal proximal tubular epithelial cell(PTEC) injury induced by aristolochic acid I (AA-I) and Aristololactam I (AL-I).
METHODS AND RESULTS:
Human PTEC cell line HK-2 was used as the subject. Cell apoptosis was evaluated by using FACS. Fibronectin (FN) and TGF-beta1 levels were assayed in the supernatant from cultured HK-2 cells by ELISA. In the blocking study, anti-TGF-beta1 neutralizing antibody was used as an antagonist. The changes of FN level and apoptosis were compared. After stimulation by 2.5 mg/L AA-I, HK-2 cells secreted TGF-beta1 at hour 12 and FN at hour 36. HK-2 cell apoptosis was detected at hour 48. Anti-TGF-beta1 neutralizing antibody (5 mg/L) could suppress AA-I induced apoptosis by 63.7%(P<0.001), and it blocked AA-I induced FN secretion by 50.2%(P<0.001). In contrast, Anti-TGF-beta1 neutralizing antibody had no effect on Aristololactam I-induced apoptosis and FN secretion, even though Aristololactam I (5 mg/L) had similar effect on these events compared to AA-I.
CONCLUSIONS:
The effects of AA-I on stimulating cell apoptosis and FN secretion are mediated by TGF-beta1. As the metabolite of that of AA-I, the cellular injury mechanism of Aristololactam I is different from that of AA-I, although it has similar effects like AA-I. The effects of Aristololactam I may be mediated by different mechanisms except TGF-beta1 pathway.
Zhongguo Zhong Yao Za Zhi. 2008 Apr;33(7):793-7.
Observation of penetration, distribution and accumulation in human renal proximal tubular epithelial cells by aristololactam-I[Pubmed:
18589784]
To study whether Aristololactam I (AL-I) can enter renal proximal tubular epithelial cells and the situation of intracellular distribution and accumulation.
METHODS AND RESULTS:
Cultured human renal proximal tubular epithelial cell line (HK-2) was used as the subject. Intracellular fluorescence from Aristololactam I and its distribution are examined by fluorescence microscopy after a treatment with different concentration of Aristololactam I, the intracellular accumulation of Aristololactam I was also investigated by incubated cells in Aristololactam I -free medium for 48 h after washing-out the media containing Aristololactam I. After treatment of Aristololactam I (concentration from 5 microg x mL(-1) to 20 microg x mL(-1)), glaucous fluorescence could be observed inside renal proximal tubular epithelial cells at 0.5 h, and the fluorescence distributed only in cytoplasm while not be observed in nuclei. Moreover, the fluorescence of Aristololactam I could be kept in cytoplasm for more than 48 h after washing out the media containing Aristololactam I .
CONCLUSIONS:
Aristololactam I is able to enter renal proximal tubular epithelial cells in short time and accumulate in cytoplasm, but not enter nuclei. This property may contribute to the cytotoxic mechanism of renal injury induced by Aristololactam I, which may partially explain the persistent renal toxicity of AAs and its metabolites in the development of aristolochic acid nephropathy.
