Studies into the Role of Alcohol in DNA Damage

(Published with kind permission from Bev Mayhew, Exec Director of FARF)

Dear FA families,

An article by KJ Patel, MD, PhD, from the University of Cambridge in the United Kingdom, was published last month in the scientific journal, Nature.
Dr. Patel, who received support from FARF for this work, studied the role of a toxic byproduct of alcohol breakdown called acetaldehyde in DNA damage.
The pathway that would repair this damage in a healthy person is not functioning right in a person with FA.

The paper, called “Fancd2 Counteracts the Toxic Effects of Naturally Produced Aldehydes in Mice” is available here. (Note: You need to be signed up to the FARF Bulletin Board to access this). Note that a separate article, written by long-time FA researcher, Hans Joeje, PhD, is included in the attachment. This article, called “Alcohol, DNA and Disease” was published as a companion piece to Dr. Patel’s article in the same issue of Nature.

Abstract: Fancd2 Counteracts the Toxic Effects of Naturally Produced Aldehydes in Mice: Reactive aldehydes are common carcinogens. They are also by-products of several metabolic pathways and, without enzymatic catabolism, may accumulate and cause DNA damage. Ethanol, which is metabolised to acetaldehyde, is both carcinogenic and teratogenic in humans. Here we find that the Fanconi anaemia DNA repair pathway counteracts acetaldehyde-induced genotoxicity in mice. Our results show that the acetaldehyde-catabolising enzyme Aldh2 is essential for the development of Fancd22/2 embryos. Nevertheless, acetaldehyde-catabolism-competent mothers (Aldh21/2) can support the development of double-mutant (Aldh22/2Fancd22/2) mice. However, these embryos are unusually sensitive to ethanol exposure in utero, and ethanol consumption by postnatal double-deficient mice rapidly precipitates bone marrow failure. Lastly, Aldh22/2Fancd22/2 mice spontaneously develop acute leukaemia. Acetaldehyde-mediated DNA damage may critically contribute to the genesis of fetal alcohol syndrome in fetuses, as well as to abnormal development, haematopoietic failure and cancer predisposition in Fanconi anaemia patients.

In an effort to better understand Dr. Patel’s work, I posed several questions via e-mail to him, which he graciously answered. I’ve included that informal Q & A below. As you’ll note, this research was done on mice, not humans, and many questions remain; however, it offers a exciting thesis that potentially explains why some blood stem cells die as a result of DNA damage.

All the best,

Bev

Q&A related to K.J. Patel’s article,”Fancd2 Counteracts the Toxic Effects of Naturally Produced Aldehydes in Mice”

Bev: Excessive maternal intake of alcohol is harmful to a fetus, regardless of FA. Given the complications generated by a defective DNA repair system that is inherent in people with FA, the potential harm to the fetus as a result of alcohol toxicity is exacerbated. Is this correct?

KJ Patel: Correct, however a mother carrying an embryo with FA would be predicted to be at unusual risk particularly in the first trimester. We do not know what level of alcohol would be safe, but one should actually consider absolute and total abstinence. Finally Asian mothers may carry the alcohol pink flushing mutation – these individuals are predicted to be at particular risk as they accumulate acetaldehyde (the toxic breakdown product of ethanol).

Bev: Maternal alcohol intake, excessive or otherwise, would not cause a child to be born with FA, however it could increase the severity of developmental defects associated with FA.

KJ Patel: Correct, Though there is some data to suggest that drinking during pregnancy may put a child at risk to acute leukemia.

Bev: This research points to several possible therapies:

Bev: Possible therapy #1. Induce the catabolism of aldehydes by induction of the relevant enzymes. KJ – what does this mean?

KJ Patel: Our paper shows that we protect oursleves for the toxic effects of acetaldehyde by a two-tier mechanism. Firstly we try to efficiently break down this chemical to something that is harmless–this is what the word “catabolism” means. There are many enzymes that do this. The most important being ALDH2 (in fact, it is the one that alcohol flushers are deficient in).
The second protective mechanism is repair by the FA proteins which come into play should the toxic chemical be allowed to accumulate and then damage DNA.
This is the key concept of the paper: a two-tier protective mechanism to protect the cells in our body from this toxin – acetaldehyde.

Bev: Possible therapy #2. Identify a drug that could mimic the damaging agent derived from alcohol to help breakdown the alcohol toxicity more quickly. Is this right?

KJ Patel: The good news is that there two ways to protect against this toxin breakdown (aldh enzymes) and DNA repair (FA proteins). So if we were able to either raise the level of the aldh enzymes in us or in fact their activity (in a way getting more out of less) then we might be able to be less reliant on the repair (which of course FA patients lack). The good news is that it might be simple and easy to achieve this because there are drugs and in fact chemicals that do this – we now have to try hard and see if this can work in our animal models.

Bev: Possible therapy #3. Find the source of aldehyde (acetaldehyde) that is being naturally produced and then intervene to prevent production.

KJ Patel: This chemical is also produced by biochemical pathways in our cells, this is probably why these enzymes (aldhs) evolved in the first place, in fact all living organisms from bacteria to humans have them. If we were able to turn down the route of natural production then again we would be left with less acetaldehyde in our cells and hence less chance to damage DNA.

Bev: I guess a larger question is: how excited should FA patients/parents be about this? What would you say to a group of parents/patients gathered in a room?

KJ Patel: I would say that I am not the best person to judge this (objectivity is on such rational issues are lost in the excitement of
discovery), you should find a sceptic and an enthusiast to give your audience a balance. BUT using the analogy of xeroderma pigmetosum (XP) which is a defect in children not too dissimilar to FA, in this condition the children are sensitive to sunlight, because the UV light damages their DNA and the XP molecules fix this. So alcohol and reactive aldehydes are in a way the sunlight equivalent for this in the context of FA.

Finally two notes of caution: Firstly the work was done in genetically engineered mice where the effects are greatly exaggerated but nevertheless reveal that there is a two tier protection mechanism. Secondly we have examined the effects of only one molecule in the family of these reactive chemicals called the aldehydes. I am sure that the other related chemicals may also be a concern for FA patients, this is what we are hard at trying to figure out right now.

 

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