TY - JOUR
T1 - Absorptivity Is an Important Determinant in the Toxicity Difference between Aristolochic Acid I and Aristolochic Acid II
AU - Kwok, Hong-Ching
AU - Tse, Hei-Tak
AU - Ng, Ka-Ki
AU - Wang, Shuangshuang
AU - Au, Chun-Kit
AU - Cai, Zongwei
AU - Chan, Wan
N1 - This project was supported by the Hong Kong Research Grants Council (GRF 16303719 and 16301923).
Publisher Copyright:
© 2025 American Chemical Society
PY - 2025/1/29
Y1 - 2025/1/29
N2 - Inadvertent exposure to aristolochic acids (AAs) is causing chronic renal disease worldwide, with aristolochic acid I (AA-I) identified as the primary toxic agent. This study employed chemical methods to investigate the mechanisms underlying the nephrotoxicity and carcinogenicity of AA-I. Aristolochic acid II (AA-II), which has a structure similar to that of AA-I, was investigated with the same methods for comparison. Despite their structural similarities, findings from cultured human cells and gut sac experiments showed that AA-I is absorbed more effectively than AA-II (∼3 times greater for AA-I than for AA-II; p < 0.001). This increased absorption, along with the previously observed higher activity of reductive activation enzymes for AA-I, results in greater DNA damage and oxidative stress, both of which are key factors in AA-related toxicity. The similar patterns of cell mortality (34.4 ± 2.3% vs 9.7 ± 0.1% for AA-I and AA-II at 80 μM; p < 0.0001), DNA adduct formation (∼3 times greater for AA-I than for AA-II; p < 0.001), and oxidative stress levels in relation to the concentrations of AA-I and AA-II indicate that the higher absorption rate of AA-I is a significant contributor to its greater toxicity. The toxicity of AA-I was also found to be further enhanced by its (natural) coexistence with AA-II. Since AA-I and AA-II differ only by a methoxy group, future research on reducing risks associated with AA exposure should focus on strategies to lower the absorption of these compounds.
AB - Inadvertent exposure to aristolochic acids (AAs) is causing chronic renal disease worldwide, with aristolochic acid I (AA-I) identified as the primary toxic agent. This study employed chemical methods to investigate the mechanisms underlying the nephrotoxicity and carcinogenicity of AA-I. Aristolochic acid II (AA-II), which has a structure similar to that of AA-I, was investigated with the same methods for comparison. Despite their structural similarities, findings from cultured human cells and gut sac experiments showed that AA-I is absorbed more effectively than AA-II (∼3 times greater for AA-I than for AA-II; p < 0.001). This increased absorption, along with the previously observed higher activity of reductive activation enzymes for AA-I, results in greater DNA damage and oxidative stress, both of which are key factors in AA-related toxicity. The similar patterns of cell mortality (34.4 ± 2.3% vs 9.7 ± 0.1% for AA-I and AA-II at 80 μM; p < 0.0001), DNA adduct formation (∼3 times greater for AA-I than for AA-II; p < 0.001), and oxidative stress levels in relation to the concentrations of AA-I and AA-II indicate that the higher absorption rate of AA-I is a significant contributor to its greater toxicity. The toxicity of AA-I was also found to be further enhanced by its (natural) coexistence with AA-II. Since AA-I and AA-II differ only by a methoxy group, future research on reducing risks associated with AA exposure should focus on strategies to lower the absorption of these compounds.
KW - Balkan endemic nephropathy
KW - DNA adduct
KW - aristolochic acids
KW - dietary exposure
KW - food contamination
UR - http://www.scopus.com/inward/record.url?scp=85216922793&partnerID=8YFLogxK
U2 - 10.1021/acs.jafc.4c10765
DO - 10.1021/acs.jafc.4c10765
M3 - Journal article
SN - 0021-8561
VL - 73
SP - 2551
EP - 2561
JO - Journal of Agricultural and Food Chemistry
JF - Journal of Agricultural and Food Chemistry
IS - 4
ER -
