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Carcinogenesis: Oxidative Stress and Carcinogenesis

Pretreatment of rats with the coffee components kahweol and cafestol protects against liver damage and oxidative stress that occur within 48 hours after exposure to carcinogenic azoxymethane.

Medical University of Vienna, Vienna, Austria; Allg. Öffentl. Krankenhaus, Wiener Neustadt, Austria; Wake Forest University, Winston-Salem, NC

Abstract

B69

It has been shown that coffee drinkers are at a reduced risk of developing cancers of several organs, primarily colon and liver, the latter also associated with protection against liver cirrhosis. Several of the >1000 coffee components have been identified as potential chemoprotectants among which an important and versatile role is played by kahweol and cafestol (K/C), two closely related diterpenes contained in coffee beans and unfiltered coffee varieties. In animals, pretreatment with K/C reduced mutagenicity/tumorigenicity of highly metabolized compounds such as the cooked food mutagen PhIP and aflatoxin B1. This may be explained by the potential of K/C to induce various beneficial changes in xenobiotic metabolism, likely resulting in decreased activation and increased detoxification of mutagens/carcinogens. K/C also enhanced the capacity of rat liver to repair alkylated DNA, e.g. resulting from exposure to nitrosamines or azoxymethane (AOM), a model carcinogen in colon and liver. Thus, we took a closer look at the initiation phase of AOM-related tumorigenesis in rat liver and at possible protection by K/C during this period. Male F344 rats were exposed to AOM (30 mg / kg body weight, i.p.) after some of them had received 0.2% of K/C in their food for 10 preceding days. Investigation at several time points during the following 48 hours revealed that AOM intoxication involved both acute hepatotoxicty (monitored by serum ALT and liver histology) and hepatic oxidative stress (monitored as lipid hydroperoxides in the ferrous oxidation in xylenol orange [FOX] assay and by ferritin levels) which may thus both play a role in AOM-related tumor initiation. The investigated parameters were apparently not modified by MNU, another alkylating carcinogen. While the ALT data suggest a biphasic course of AOM-related liver damage with a peak at 12 hrs and a re-increase during day 2, increases in the FOX assay were not observed until after 24 hrs post injection (maximum at 36 hrs), suggesting the involvement of more than one mechanism of damage. Also, the FOX assay data were not in agreement with the largely unmodified hepatic levels of TBARS and malondialdehyde, two further indicators of oxidative stress. Importantly, K/C mitigated all described signs of AOM-related toxicity, e.g. the >3-fold maximum increase in the FOX assay was reduced to 2-fold and the up to 5-fold increase in liver ferritin was essentially prevented. Thus, these data further substantiate the versatility of K/C-related chemoprotection. Protection by K/C against oxidative stress may in part be explained by the ca. 3-fold enhancement of hepatic glutathione that was maintained throughout the 48 hr observation period. Supported in part by the Austrian Herzfeldersche Familienstiftung