High and complementary expression patterns of alcohol and aldehyde dehydrogenases in the gastrointestinal tract

Abstract

Although the etiology of the neurodegenerative events in Parkinson's disease (PD) remains largely unknown, evidence suggests that both environmental and genetic factors are involved. The disease is characterized by loss of dopamine (DA) neurons in substantia nigra pars compacta (SNpc) and later in the ventral tegmental area. These events are accompanied by progressive loss of DA innervation of nucleus caudatus and putamen, resulting primarily in movement disabilities. However, degenerative events are also known to involve other neuron populations. Suggested causes for the neurodegeneration include oxidative stress, misfolded proteins, inflammation, mitochondrial and ubiquitin-proteasome dysfunction and impaired protection against potentially harmful substances. Recently however, several genes have been identified in which mutations are either linked to or associated with disease, shifting the weight of evidence towards genetic causes and complex genetic risk factors in PD. Parkinson-linked genes include a-synuclein (SNCA), DJ-1, Parkinson's disease (PD) is a heterogeneous movement disorder characterized by progressive degeneration of dopamine neurons in substantia nigra. We have previously presented genetic evidence for the possible involvement of alcohol and aldehyde dehydrogenases (ADH; ALDH) by identifying genetic variants in ADH1C and ADH4 that associate with PD. The absence of the corresponding mRNA species in the brain led us to the hypothesis that one cause of PD could be defects in the defense systems against toxic aldehydes in the gastrointestinal tract. We investigated cellular expression of Adh1, Adh3, Adh4 and Aldh1 mRNA along the rodent GI tract. Using oligonucleotide in situ hybridization probes, we were able to resolve the specific distribution patterns of closely related members of the ADH family. In both mice and rats, Adh4 is transcribed in the epithelium of tongue, esophagus and stomach, whereas Adh1 was active from stomach to rectum in mice, and in duodenum, colon and rectum in rats. Adh1 and Adh4 mRNAs were present in the mouse gastric mucosa in nonoverlapping patterns, with Adh1 in the gastric glands and Adh4 in the gastric pits. Aldh1 was found in epithelial cells from tongue to jejunum in rats and from esophagus to colon in mice. Adh3 hybridization revealed low mRNA levels in all tissues investigated. The distribution and known physiological functions of the investigated ADHs and Aldh1 are compatible with a role in a defense system, protecting against alcohols, aldehydes and formaldehydes as well as being involved in retinoid metabolism.

Involvement of Dopamine D2 Receptors in Addictive-Like Behaviour for Acetaldehyde

“…at doses of 100 mg/kg [69], [70]. According to our data, ACD intake reached mean values of 665,3 mg/kg, within the 20 min-operant session, and it is conceivable that such chronic and increasing intake of ACD can overwhelm the metabolic barrier constituted by epithelial aldehyde dehydrogenase (ALDH1), a low Km ACD-oxidizing enzyme expressed in gastrointestinal tract [71]. Systemic absorption after ACD oral ingestion has been already demonstrated by previous studies on ACD self-administration by Peana and colleagues [12].…”

Ethanol metabolism and its effects on the intestinal epithelial barrier

“…The mucosa of the oral cavity, esophagus, and stomach is characterized by a high expression of class IV ADH . The esophagus has the highest ADH activity in the GI tract, similar to that of the liver and approximately four times that of the stomach . In small and large intestinal mucosa, class I ADH is predominant, with a Km of 1–2 mM for ethanol .…”

Cluster Headache is Associated With the Alcohol Dehydrogenase 4 (ADH4) Gene

“…In humans, ADHs are encoded by at least 7 different genes (ADH1A, 1B, 1C, 4, 5, 6, and 7) located on chromosome 4q21‐q25, in a head‐to‐tail array 13 . ADHs appear to participate in a general defense toward alcohols and aldehydes, without generating toxic radicals 14 . These enzymes are involved also in other metabolism such as hydroxy fatty acids, steroids, and biogenic amines 15 …”