Study on the mechanism of the chemical carcinogenesis of cirrhotic liver

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The effects of reduced glutathione (GSH) and ethanol on aflatoxin B_1 AFB_1)-induced DNA single strand breaks and AFB_1-DNA adduct formation were studied in primary cultured hepatocytes. Buthionine sulphoximine (BSO) decreased intracellular GSH to 13% of those of control levels, increased DNA fragmentation of AFB_1-treated hepatocytes by over 17% of those without BSO. Thus a decrease in hepatocyte GSH levels increased AFB_1-induced DNA damage. Although ethanol in itself did not induce DNA damage, a combination of BSO and ethanol increased the percentage by over 23% of that with BSO only. BSO significantly enhanced the formation of [^3H]AFB_1-DNA adducts and ethanol further increased it in the presence of BSO, whereas ethanol did not affect the amount of GSH, total cytochrome P-450, glutathione S-transferase and epoxide hydrolase in cultured hepatocytes. However, GSH-depleted rat hepatocytes exposed to ethanol significantly increased the level of cytochrome P450IIIA, which activates AFB_1. The enhancing effects of ethanol in the presence of BSO are probably due to the induction of this enzyme in rat hepatocytes.