br Acetaldehyde One of the

Acetaldehyde One of the most common environmental aldehydes is acetaldehyde (CH2CHO). Acetaldehyde, which is highly volatile, has been classified as a Group I human carcinogen by the International Agency for Research on Cancer [30]. Aldehydes can form DNA adducts, including ring-open forms of crotonaldehyde propanodeoxyguanosines, which can be generated from crotonaldehyde or two successive reactions with individual acetaldehyde molecules [31,32]. These ring-open forms can dimerize with other guanosine residues, resulting in interstrand crosslink (ICL) formation between DNA strands [32–34]. There are other effects of aldehydes on cells, including adducts covalently added to proteins, especially by 4-hydroxy-nonenal (4-HNE) [34]. ICL crosslinks can lead to genotoxic effects due to DNA damage and protein adducts can disrupt cellular signaling and result in protein aggregation and protein unfolding responses. These effects have been implicated in pathological processes such as myocardial infarction and atherosclerosis [35–39]. Intracellular aldehydes are derived from both exogenous and endogenous sources (see Table 1). The major exogenous sources of aldehydes are likely to be direct exposure to environmental aldehydes including acrolein, formaldehyde and acetaldehyde. These aldehydes can be present in burned oil, industry glue and new buildings, as well as M344 sale fuel and fragrances [30,31,33,40–42]. More sources of aldehydes in the environment as well as those generated endogenously are detailed in Table 1. Besides exposure via industrial or environmental inhalation or contact, acetaldehyde exposure occurs through ingestion. This can occur by consumption of acetaldehyde directly (as in foods containing acetaldehyde), by drinking ethanol, or by ethanol produced by the gut microbiota. Acetaldehyde is directly ingested by consuming ripe fruits, coffee, and bread, which derive their fruity aroma from acetaldehyde. Vinegar and foods pickled with vinegar also contain acetaldehyde, as well as fermented foods such as yogurt [30]. An important source of acetaldehyde is from ethanol metabolism [44]. Ingested ethanol is oxidized mainly in the liver to acetaldehyde by alcohol dehydrogenase, which is coupled to reduction of NAD+ to NADH. Aldehyde dehydrogenase (ALDH) further oxidizes acetaldehyde to acetic acid, again in a reaction coupled to NAD+ reduction. The gut microbiome ferments sugars to form ethanol that is then converted to acetaldehyde [43]. Finally, endogenous production of acetaldehyde can occur as a result of several metabolic processes (reviewed in [31]), for example under inflammatory conditions [45]. Myeloperoxidase in neutrophils and myeloid progenitors generates acetaldehyde as a byproduct of hypochlorous acid and tyrosyl radical production. In times of oxidative stress, when the mitochondria are unable to generate enough ATP, deoxyribose phosphate aldolase can metabolize 2-deoxy-d-ribose-5 phosphate to glyceraldehyde-3-phosphate and acetaldehyde, which allows cells to use nucleotides to replenish ATP levels [46]. Other potential sources of endogenously generated acetaldehyde are products of lipid peroxidation, carbohydrate/ascorbate autoxidation, carbohydrate metabolism, amine oxidases and cytochrome P-450 catalyzed metabolism [31]. Acetaldehyde has been found to induce ICL in both mammalian and rodent cell lines, and to activate the FA pathway [47–49]. Acetaldehyde-induced DNA damage colocalizes with RAD51/FANCR [47], and increases FANCD2 monoubiquitination and BRCA1/FANCS activation via phosphorylation [48,49]. These studies demonstrate that acetaldehyde may be a critical aldehyde in activation of the FA pathway.
The aldehyde dehydrogenase (ALDH) enzyme family In humans, ALDH enzymes comprise a 19 isoenzyme family of proteins with different patterns of substrate specificity, tissue and cell distribution and subcellular localization [50]. Given the widespread sources of exogenous and endogenous aldehydes as well as the ability of these compounds to deleteriously modify both DNA and proteins, the expression of aldehyde dehydrogenase (ALDH) enzymes is necessary in all tissues. ALDH oxidize aldehydes to form respective acidic derivatives of their substrates. Because of the variety of reactive aldehydes, ALDH isoforms with different specificities are needed. The substrate specificity and redundancy of these isoenzymes has not been fully characterized (see review [51]). The focus of this review will be on ALDH2, the enzyme which preferentially detoxifies acetaldehyde, as denoted by its Km being 900-fold lower than that of ALDH1, another enzyme that can detoxify acetaldehyde [52]. ALDH2 is encoded by nuclear DNA, but is localized inside mitochondria, and is important in reducing oxidative stress [52]. ALDH2 uses NAD+ as co-enzyme and oxidizes acetaldehyde to acetic acid [53]. ALDH2 expression in mice is similar to that of humans, where it is present in liver, esophagus, lung, pancreas, brain and heart [54–56]. ALDH2 is a homotetrameric molecule localized in the mitochondrial matrix. ALDH2 synthesis is continuously required, because some reactive aldehyde substrates, like 4-HNE, bind to and inactivate the enzyme, thus rendering it unable to catalyze further reactions [57].