INCREASE THE RISK OF COLON CANCER VIA FOLATE DEFICIENCY

MICROBIALLY PRODUCED ACETALDEHYDE FROM ETHANOL MAY INCREASE THE RISK OF COLON CANCER VIA FOLATE DEFICIENCY Nils H OMANN,Jyrki T ILLONEN and Mikko S ALASPURO*

Research Unit of Alcohol Diseases,Helsinki University Central Hospital,Helsinki,Finland

High alcohol and low folate intake are independent risk factors for colorectal cancer.Acetaldehyde has been postu-lated to be a factor responsible for ethanol-associated carci-nogenesis.High levels of acetaldehyde accumulate in the large intestine via the microbial oxidation of alcohol.Acetal-dehyde degrades folate in vitro.Thus,it is possible that high intracolonic acetaldehyde levels break down folate in the colon.Our aim was to test the effect of high alcohol and acetaldehyde concentrations in the gut on systemic and local intestinal folate levels in rats.Twenty rats received3g/kg of ethanol twice a day for2weeks with or without concomitant cipro?oxacin administration.Twenty control rats received saline with or without cipro?oxacin.All rats were fed a diet with normal folate content.Alcohol treatment led to very high intracolonic acetaldehyde levels(387?185?M),which were markedly decreased by concomitant cipro?oxacin treatment(21?4?M).Erythrocyte,serum and small intes-tinal folate levels were unaffected by alcohol treatment.Al-cohol administration decreased signi?cantly colonic mucosal folate levels by48%,and this effect was prevented by cipro-?oxacin.We conclude that alcohol administration for2 weeks leads to local folate de?ciency of colonic mucosa in rats,most probably via the degradation of folate by the high levels of acetaldehyde microbially produced from ethanol. Our?ndings offer a unique explanation for the increased risk of colonic cancer associated with alcohol intake and folate de?ciency.Int.J.Cancer86:169–173,2000.

?2000Wiley-Liss,Inc.

Dietary factors have been estimated to account for up to90%of colorectal cancer cases(Doll and Peto,1981).Among general dietary factors,such as a low vegetable and fresh fruit diet or high fat and red meat intake,special attention has been paid to dimin-ished folic acid intake.In epidemiological studies,a decreased folate status has been associated with an increased risk of neoplas-tic transformation(Giovannucci et al.,1995).Another suspected risk factor for colorectal cancer is alcohol.Several studies have shown an increased cancer risk for subjects with high alcohol consumption(Longnecker et al.,1990;Kune and Vitetta,1992). Although these?ndings have not been con?rmed in some other studies,there is general agreement that a slight and signi?cant ethanol-associated cancer risk may exist,particularly for the left-sided colon and rectum.

The pathogenic mechanisms of the increased cancer risk in folate de?ciency have been partly elucidated.Folate is a crucial methyl group donor for many transmethylation reactions in the human body.Diminished folate leads to hypomethylation of the DNA,a modi?cation of the DNA that has been observed in several experimental cancer models and in human cancers(Kim et al.,1997;Goelz et al.,1985).The mechanisms of ethanol-associated carcinogenesis are less clear.There are several pos-sible candidates in alcoholics,such as general immune de?-ciency,low intake of possible cancer-protective substances and induction of metabolizing enzymes such as cytochrome P4502E1(Blot,1992).Moreover,acetaldehyde,the?rst metab-olite of alcohol,is a highly toxic and carcinogenic compound, which also might be a factor underlying ethanol-associated carcinogenesis(Seitz et al.,1990).Acetaldehyde is produced in the human body mainly by the oxidation of ethanol via alcohol http://m.wendangku.net/doc/4dedb714eefdc8d376ee32ef.htmlually,it is rapidly metabolized by aldehyde dehydrogenases to acetate.Thus,the systemic levels of acetal-dehyde in the human body are very low.However,very high levels of acetaldehyde can accumulate locally in the colon through the microbial oxidation of alcohol(Salaspuro,1996). High acetaldehyde levels catabolize folate via cleavage at the C9–N10bond(Shaw et al.,1989).Thus,it is possible that the high local intracolonic acetaldehyde levels break down folate in the colon.Via this mechanism,folate de?ciency and high alco-hol intake might cause an increased colon cancer risk through a unifying and synergistic mechanism.

Our objective was to investigate the effect of high alcohol and acetaldehyde concentrations in the gut on systemic and local intestinal folate levels in rats.

MATERIAL AND METHODS

Animals

Forty male6-month-old Wistar rats(strain Hsd/wi barrier)were randomly divided into4groups.Group I(n?10)was intubated intragastrically twice a day with a volume of14ml saline/kg body weight on14consecutive days.Group II(n?10)was treated as group I with concomitant intubation of50mg/kg body weight of cipro?oxacin at the same volume.Group III(n?10)was intu-bated with the same volume of ethanol(3g/kg,38%v/v),and group IV received the same amount of ethanol as group III with50 mg/kg body weight of cipro?oxacin in the same volume.Intuba-tions were carried out every12hr at9:00AM and9:00PM.All animals were kept in plastic cages in conventional conditions. Room temperature was maintained at22?2°C,and rats were kept in a12hr light–dark cycle.Rats had free access to tap water and standard chow(Altromin,Lage,Germany)with a folate content generally accepted as meeting the basal dietary requirement for rats(2mg/kg diet).The general condition and behavior,body weight,food,folate and?uid intake were recorded daily.Rats were killed after anesthesia with1mg/kg phenobarbital on day14of the study,45min after the last intubation.Blood(10ml,5ml to serum vacutainer tubes and5ml to tubes containing0.06ml EDTA)was collected by heart puncture using a small syringe.Our study was performed according to the institutional guidelines and principles of the Animal Care Unit of the University of Helsinki and ap-proved by the local ethical committee of the University of Helsinki and by the Committee on Animal Experimentation of the Country Council.

Colonic,small intestinal and blood ethanol and acetaldehyde levels

The cecum was opened longitudinally,and approximately1.5 ml of colonic content were immediately transferred in a pre-cooled Eppendorf tube containing50?l of6M perchloric acid, to precipitate proteins and to stop the enzymatic conversion of ethanol to acetaldehyde.The colonic content was spun down rapidly on a pre-cooled table centrifuge(2,400g for20sec), and475?l of the supernatant were immediately transferred into

Grant sponsors:http://m.wendangku.net/doc/4dedb714eefdc8d376ee32ef.htmldred Stiftung;Deutsche Krebshilfe;Yrj¨o Jahns-son Foundation;Finnish Foundation for Alcohol Studies;Helsinki Univer-sity Central Hospital Research Funds;Sigrid Juselius Foundation.

*Correspondence to:Research Unit of Alcohol Diseases,Helsinki Uni-versity Central Hospital,PL345,FIN-00029HYKS,Helsinki,Finland. Fax:?358-9-47174099.E-mail:mikko.salaspuro@helsinki.?

Received20August1999;Revised28October1999

Int.J.Cancer:86,169–173(2000)?2000Wiley-Liss,

INCREASE THE RISK OF COLON CANCER VIA FOLATE DEFICIENCY

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