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Induction of hepatic nodules in the rat by aristolochic acid
M R Rossiello1, E Laconi, P M Rao
1Department of Pathology, University of Toronto, Ontario, Canada.
Abstract:
Aristolochic acid (AA), used as an anti-inflammatory agent in the past, is known to be mutagenic and carcinogenic to several organs of the rat, including forestomach, renal pelvis and urinary bladder. However, despite the induction of DNA adducts in the liver, no carcinogenic potential of AA has been reported in the latter organ. The present study was based on the rationale that the lack of carcinogenicity of AA to the liver could be because this chemical may not be necrogenic at the doses examined and liver cell proliferation has been established as an essential component for initiation of liver carcinogenesis in the rat. The results indicated that AA is non-necrogenic to the rat liver. However, a single non-necrogenic dose of AA (10 mg/kg b.w., i.p.) given 18 hours after 2/3 partial hepatectomy initiated liver cell carcinogenesis. The initiated cells are promotable with 1% dietary orotic acid, a liver tumor promoter, to form glutathione-S-transferase 7-7 positive hepatic foci and nodules.
Insights
Aristolochic acid (AA) is not necrogenic to rat livers. However, AA can initiate liver cell carcinogenesis after partial hepatectomy, and these initiated cells can be promoted to form liver tumors.
Area of Science:
- Toxicology
- Hepatocarcinogenesis
- Chemical carcinogenesis
Background:
- Aristolochic acid (AA) is a known mutagen and carcinogen, inducing tumors in various rat organs.
- Despite DNA adduct formation in the liver, AA has not shown carcinogenic potential in this organ.
- Liver cell proliferation is crucial for initiating liver carcinogenesis in rats.
Purpose of the Study:
- To investigate the potential of Aristolochic acid (AA) to initiate liver carcinogenesis.
- To determine if AA is necrogenic to rat liver cells.
- To explore the role of liver cell proliferation in AA-induced hepatocarcinogenesis.
Main Methods:
- Administering a single non-necrogenic dose of AA (10 mg/kg b.w., i.p.) 18 hours after 2/3 partial hepatectomy in rats.
- Assessing the promotion of initiated cells using 1% dietary orotic acid, a known liver tumor promoter.
- Identifying glutathione-S-transferase 7-7 positive hepatic foci and nodules as indicators of carcinogenesis.
Main Results:
- Aristolochic acid (AA) was found to be non-necrogenic to the rat liver.
- A single, non-necrogenic dose of AA initiated liver cell carcinogenesis following partial hepatectomy.
- Dietary orotic acid promoted the initiated cells, leading to the formation of hepatic foci and nodules.
Conclusions:
- Aristolochic acid (AA) can initiate liver carcinogenesis in rats, even at non-necrogenic doses, provided there is concurrent liver cell proliferation.
- The process of AA-induced hepatocarcinogenesis is promotable by agents like orotic acid.
- This study elucidates a mechanism for AA's carcinogenic potential in the liver, previously underestimated.