Annotated PGx Gene Information for ALDH1A1
Submitted by: Ryan Owen (PharmGKB)
Reviewed by: Under Review
Submitted date: Feb 21, 2008
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| Gene HGNC Name: | ALDH1A1 |
|---|---|
| Gene Common Name: | aldehyde dehydrogease, ALDH1, RALDH1 |
| Introductory Information: | ALDH1A1 is one member of a family of aldehyde dehydrogenases, and is also known as the cytosolic aldehyde dehydrogenase. The human ortholog of this enzyme was first purified in 1979 [224930], and the genomic structure and protein length (501 amino acids) were described ten years later [2591967]. ALDH1A1 shows strong tissue expression in the liver, but is also constitutively expressed in other tissues, including erythrocytes, eye, and brain [10971205]. Aldehyde dehydrogenases are of interest due to their important and diverse physiological roles, which often include the detoxification of metabolic intermediates from an aldehyde form to a carboxylic acid form. ALDH1A1 has been shown to play a role in alcohol metabolism [17718394]. The alcohol metabolism process is essentially a two step process: first alcohol is converted to acetaldehyde by an alcohol dehydrogenase family member, and then the acetaldehyde is converted to acetate by an aldehyde dehydrogenase (ALDH1A1 or ALDH2) [17718394]. The intermediate metabolite, acetaldehyde, is thought to be toxic at high levels, and it may be responsible for some of the adverse reactions associated with alcohol such as facial flushing, nausea, and an increased heart rate [17718394]. An accumulation of acetaldehyde can occur either due to a hyperactive alcohol dehydrogenase enzyme, or an impaired aldehyde dehydrogenase enzyme [17718394]. Although some genetic variation has been described for ALDH1A1 (see variant pages), it appears that genetic variation in ALDH2 plays a more important role in determining predisposition towards alcoholism [17718394]. ALDH1A1 is also involved in the retinol (vitamin A) metabolic pathway [12851412]. The retinol pathway and the ethanol pathway share considerable overlap, and ALDH1A1 is involved in the conversion of retinaldehyde to retanoic acid (RA) [12851412]. Vitamin A (retinol) can be converted to retinal by alcohol dehydrogenase enzymes, and then further converted to RA by ALDH1A1 or other aldehyde dehydrogenases [10880953]. Retinoic Acid is involved in a number of physiological processes including cell growth and differentiation [10971205 10880953]. RA exerts its effect on the transcriptional level, by binding to retinoid receptors RAR and/or RXR, which often form a heterodimer [10880953]. The RAR/RXR heterodimer is then able to transcriptionally regulate several genes. There may be some interactions between retinol and ethanol metabolic pathways, which could potentially play a role in fetal alcohol syndrome [9802541]. ALDH1A1 has also been shown to be involved in the resistance to the chemotherapeutic agent cyclophosphamide (CP) and its derivatives [15237855]. CP is used in the treatment of several types of cancer [15237855]. CP is converted to 4-hydroxycyclophosphamide by several different CYP enzymes, and the 4-hydroxy-CP which can intraconvert with aldophosphamide [15237855]. Aldophosphamide can undergo several metabolic fates, including the formation of acrolein and phosphoramide mustard, both of which are cytotoxic alkylating agents [15237855]. Alternatively, aldophosphamide can be metabolized by ALDH1A1 (or other aldehyde dehydrogenases) to carboxyphosphamide [15237855]. This is considered to be a detoxification step, as carboxyphosphamide is not cytotoxic [10469894]. An increase in expression of ALDH1A1 has been shown to be correlated with CP-resistant cancers in patients [16918308], and in vitro evidence suggests that tranfection with ALDH1A1 can be sufficient to confer resistance to CP-induced cytotoxicity [10469894]. |
| Key PubMed IDs: | 10971205 17718394 12851412 10880953 15237855 |
| Key Pathways: | Cyclophosphamide Pathway (PD) , Ifosfamide Pathway (PD) |
| Drugs/Substrates: | acetaldehyde , retinaldehyde, aldophosphamide |
| Phenotypes/Diseases: | Alcoholism |
| Important Variants: | ALDH1A1*2 , ALDH1A1*3 |