Alcoholmediated Carcinogenesis

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Alcoholmediated Carcinogenesis

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Rats and hamsters inhaling acetaldehyde developed nasal adenoCA and SCC. It interferes with DNA synthesis/repair resulting in gross chromosomal aberrations ... – PowerPoint PPT presentation

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Title: Alcoholmediated Carcinogenesis

1
Alcohol-mediated Carcinogenesis

Grand Rounds
David Tran
5/9/08

2
Epidemiology
3
Alcohol-associated cancers in humans
4
and the drunken rodent
5
Ethanol Metabolism and Ethanol-mediated
Carcinogenesis
Liver
6
Acetaldehyde is a carcinogen

Rats and hamsters inhaling acetaldehyde developed
nasal adenoCA and SCC.
It interferes with DNA synthesis/repair resulting
in gross chromosomal aberrations
It binds to proteins including those in cell
cycle and DNA repair and impairs their functions.
It binds DNA forming stable DNA adducts

7
Acetaldehyde-DNA Adducts
8
Alcoholics have higher levels of DNA adducts
9
Higher acetaldehyde Higher Cancer Risks ?

Ethanol oxidized by microbes in the GI tract to
acetaldehyde.
After ½ bottle of wine (0.5g/kg), saliva
acetaldehyde can reach 50-100uM (mutagenic
concentration, 10-100 fold gt blood).
In piglets and rats colon, acetaldehyde can
reach 250-500uM due to large amount of bacteria.
Higher colon acetaldehyde, more injury, more
accelerated carcinogenesis in conventional
animals gt germ-free animals

10
Higher acetaldehyde Higher Cancer Risks ?

In Humans
ALDH21 normal
ALDH22 inactive (K487Q)
40-50 Asians are heterozygous or homozygous 22.
22 Homozygotes are intolerant of ethanol.
Heterozygotes can tolerate some ethanol but have
3-fold higher serum acetaldehyde than 21
homozygotes.

11
Higher acetaldehyde Higher Cancer Risks ?
12
Oxidative Stress
13
Hepatocarcinogenesis

Oxidative stress Cirrhosis are important
factors.
Acetaldehyde less important.
In alcohol-fed rodents, pre-malignant lesions
(enzyme-altered foci) populated by hepatic
progenitor cells (oval cells) appear before HCC.
Oval cells are stimulated by TNFa and TGFb
(markedly upregulated in ALD, in part by
acetaldehyde and ROS), both of which act as
growth inhibitors of hepatocytes

14
Nutritional Factors

Chronic alcoholism depletes vit A and RA through
increased catabolism by ethanol induced CYP2E1.
Ethanol impairs many aspects of methyl group
transfer in gene regulation.

15
An Overview
16
References