Aristolochic acid I promoted clonal expansion but did not induce hepatocellular carcinoma in adult rats
| العنوان: | Aristolochic acid I promoted clonal expansion but did not induce hepatocellular carcinoma in adult rats |
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| المؤلفون: | Xiao-lan Ding, Fangfang Yang, Yong-zhen Liu, Likun Gong, Ze-an Zhang, Zhongping Deng, Xinming Qi, Jin Ren, Pan Yu, Lu Liu, Xin Wang, Henglei Lu, Guozhen Xing |
| المصدر: | Acta Pharmacol Sin |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, medicine.medical_specialty, Carcinoma, Hepatocellular, Carcinogenesis, Kidney, Article, Nephrotoxicity, Rats, Sprague-Dawley, DNA Adducts, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Stomach Neoplasms, Oral administration, Internal medicine, Intestinal Neoplasms, medicine, Animals, Bioassay, Pharmacology (medical), Carcinogen, Cell Proliferation, Pharmacology, business.industry, Liver Neoplasms, Stomach, General Medicine, Glutathione, medicine.disease, Kidney Neoplasms, Intestines, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Glutathione S-Transferase pi, Liver, chemistry, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Carcinogens, Hepatocytes, Aristolochic Acids, Animal studies, business, Mutagens |
| الوصف: | Aristolochic acid I (AAI) is a well-known nephrotoxic carcinogen, which is currently reported to be also associated with hepatocellular carcinoma (HCC). Whether AAI is a direct hepatocarcinogen remains controversial. In this study we investigated the association between AAI exposure and HCC in adult rats using a sensitive rat liver bioassay with several cofactors. Formation of glutathione S-transferase placental form-positive (GST-P(+)) foci was used as the marker for preneoplastic lesions/clonal expansion. We first conducted a medium-term (8 weeks) study to investigate whether AAI had any tumor-initiating or -promoting activity. Then a long-term (52 weeks) study was conducted to determine whether AAI can directly induce HCC. We showed that oral administration of single dose of AAI (20, 50, or 100 mg/kg) in combination with partial hepatectomy (PH) to stimulate liver proliferation did not induce typical GST-P(+) foci in liver. In the 8-week study, only high dose of AAI (10 mg · kg(−1) · d(−1), 5 days a week for 6 weeks) in combination with PH significantly increased the number and area of GST-P(+) foci initiated by diethylnitrosamine (DEN) in liver. Similarly, only high dose of AAI (10 mg· kg(−1)· d(−1), 5 days a week for 52 weeks) in combination with PH significantly increased the number and area of hepatic GST-P(+) foci in the 52-week study. No any nodules or HCC were observed in liver of any AAI-treated groups. In contrast, long-term administration of AAI (0.1, 1, 10 mg· kg(−1)· d(−1)) time- and dose-dependently caused death due to the occurrence of cancers in the forestomach, intestine, and/or kidney. Besides, AAI-DNA adducts accumulated in the forestomach, kidney, and liver in a time- and dose-dependent manner. Taken together, AAI promotes clonal expansion only in the high-dose group but did not induce any nodules or HCC in liver of adult rats till their deaths caused by cancers developed in the forestomach, intestine, and/or kidney. Findings from our animal studies will pave the way for further large-scale epidemiological investigation of the associations between AA and HCC. |
| تدمد: | 1745-7254 1671-4083 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c37b3d5118e00f484ab2d57d350b1b9bTest https://doi.org/10.1038/s41401-021-00622-7Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c37b3d5118e00f484ab2d57d350b1b9b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17457254 16714083 |
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