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Carcinogenesis Advance Access published online on October 24, 2003
Carcinogenesis, doi:10.1093/carcin/bgg194
© 2003 by Oxford University Press
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© 2003 Oxford University Press

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Grapefruit juice intake does not enhance but rather protects against aflatoxin B1-induced liver DNA damage through reduction of hepatic CYP3A activity

Masaaki Miyata 1*, Hiroki Takano 1, Lian Q. Guo 1, Kiyoshi Nagata 1, and Yasushi Yamazoe 1

1 Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, Sendai, 980-8578, Japan

* Corresponding author. E-mail: miyata{at}mail.pharm.tohoku.ac.jp.

Received 19 June 2003 ; revised 27 September 2003 ; accepted 7 October 2003

Abstract

Influence of grapefruit juice intakes on aflatoxin B1(AFB1)-induced liver DNA damage was examined using a comet assay in F344 rats given 5 mg/kg of AFB1 by gavage. Rats allowed free access to grapefruit juice for 5 days prior to the administration resulted in clearly reduced DNA damage in liver to 65% of the level in rats that did not receive grapefruit juice. Furthermore, rats treated with grapefruit juice-extract (100 mg/kg, p.o.) for 5 days prior to the AFB1 treatment also reduced the DNA damage to 74% of the level in rats that did not receive grapefruit juice. No significant differences in the portal blood and liver concentration of AFB1 were observed between grapefruit juice intake rats and the controls. In an Ames assay with AFB1 using Salmonella typhimurium TA98, lower numbers of revertant colonies were detected with hepatic microsomes prepared from rats administered grapefruit juice, compared to those from control rats. Microsomal testosterone 6{beta}-hydroxylation was also lower with rats given grapefruit juice than with control rats. Immunoblot analyses showed a significant decrease in hepatic CYP3A content, but not CYP1A and CYP2C content, in microsomes of grapefruit juice-treated rats than in non-treated rats. No significant difference in hepatic glutathione S-transferase (GST) activity and glutathione content was observed in the two groups. GSTA5 protein was not detected in hepatic cytosols of the two groups. In microsomal systems, grapefruit juice-extract inhibited AFB1-induced mutagenesis in the presence of the microsomal activation system from livers of humans as well as rats.

These results suggest that grapefruit juice intake suppresses AFB1-induced liver DNA damage through inactivation of the metabolic activation potency of AFB1 in rat liver.


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