Reactive oxygen species (ROS) are continuously generated within living systems and the inability to manage ROS load leads to elevated oxidative stress and cell damage. Oxidative stress is coupled to the oxidative degradation of lipid membranes, also known as lipid peroxidation. This process generates over 200 types of aldehydes, many of which are highly reactive and toxic. Aldehyde dehydrogenases (ALDHs) metabolize endogenous and exogenous aldehydes and thereby mitigate oxidative/electrophilic stress in prokaryotic and eukaryotic organisms. ALDHs are found throughout the evolutionary gamut, from single celled organisms to complex multicellular species. Not surprisingly, many ALDHs in evolutionarily distant, and seemingly unrelated, species perform similar functions, including protection against a variety of environmental stressors like dehydration and ultraviolet radiation. The ability to act as an ‘aldehyde scavenger’ during lipid peroxidation is another ostensibly universal ALDH function found across species. Up-regulation of ALDHs is a stress response in bacteria (environmental and chemical stress), plants (dehydration, salinity and oxidative stress), yeast (ethanol exposure and oxidative stress), Caenorhabditis elegans (lipid peroxidation) and mammals (oxidative stress and lipid peroxidation). Recent studies have also identified ALDH activity as an important feature of cancer stem cells. In these cells, ALDH expression helps abrogate oxidative stress and imparts resistance against chemotherapeutic agents such as oxazaphosphorine, taxane and platinum drugs. The ALDH superfamily represents a fundamentally important class of enzymes that significantly contributes to the management of electrophilic/oxidative stress within living systems. Mutations in various ALDHs are associated with a variety of pathological conditions in humans, underscoring the fundamental importance of these enzymes in physiological and pathological processes.

Cytokines play a very important role in nearly all aspects of inflammation and immunity. The term ‘interleukin’ (IL) has been used to describe a group of cytokines with complex immunomodulatory functions — including cell proliferation, maturation, migration and adhesion. These cytokines also play an important role in immune cell differentiation and activation. Determining the exact function of a particular cytokine is complicated by the influence of the producing cell type, the responding cell type and the phase of the immune response. ILs can also have pro- and anti-inflammatory effects, further complicating their characterisation. These molecules are under constant pressure to evolve due to continual competition between the host’s immune system and infecting organisms; as such, ILs have undergone significant evolution. This has resulted in little amino acid conservation between orthologous proteins, which further complicates the gene family organisation. Within the literature there are a number of overlapping nomenclature and classification systems derived from biological function, receptor-binding properties and originating cell type. Determining evolutionary relationships between ILs therefore can be confusing. More recently, crystallographic data and the identification of common structural motifs have led to a more accurate classification system. To date, the known ILs can be divided into four major groups based on distinguishing structural features. These groups include the genes encoding the IL1-like cytokines, the class I helical cytokines (IL4-like, γ-chain and IL6/12-like), the class II helical cytokines (IL10-like and IL28-like) and the IL17-like cytokines. In addition, there are a number of ILs that do not fit into any of the above groups, due either to their unique structural features or lack of structural information. This suggests that the gene family organisation may be subject to further change in the near future.

Aldehyde dehydrogenase 2 (ALDH2) is the major enzyme that metabolizes acetaldehyde produced from alcohol metabolism. Approximately 40~50% of East Asians carry an inactive ALDH2 gene and exhibit acetaldehyde accumulation after alcohol consumption. However, the role of ALDH2 deficiency in the pathogenesis of alcoholic liver injury remains obscure. In the present study, wild-type and ALDH2−/− mice were subjected to ethanol feeding and/or carbon tetrachloride (CCl4) treatment, and liver injury was assessed. Compared with wild-type mice, ethanol-fed ALDH2−/− mice had higher levels of malondialdehyde-acetaldehyde (MAA) adduct and greater hepatic inflammation, with higher hepatic IL-6 expression but surprisingly lower levels of steatosis and serum ALT. Higher IL-6 levels were also detected in ethanol-treated precision-cut-liver-slices from ALDH2−/− mice and in Kupffer cells isolated from ethanol-fed ALDH2−/− mice than those levels in wild-type mice. In vitro incubation with MAA enhanced the LPS-mediated stimulation of IL-6 production in Kupffer cells. In agreement with these findings, hepatic activation of the major IL-6 downstream signaling molecule signal transducer and activator of transcription 3 (STAT3) was higher in ethanol-fed ALDH2−/− mice than in wild-type mice. An additional deletion of hepatic STAT3 increased steatosis and hepatocellular damage in ALDH2−/− mice. Finally, ethanol-fed ALDH2−/− mice were more prone to CCl4-induced liver inflammation and fibrosis than ethanol-fed wild-type mice. Conclusions: ALDH2−/− mice are resistant to ethanol-induced steatosis but prone to inflammation and fibrosis via MAA-mediated paracrine activation of IL-6 in Kupffer cells. These findings suggest that alcohol, via acetaldehyde and its associated adducts, stimulates hepatic inflammation and fibrosis independent from causing hepatocyte death, and that ALDH2-deficient individuals may be resistant to steatosis and blood ALT elevation, but are prone to liver inflammation and fibrosis following alcohol consumption.

The estrogenic effects of bisphenol A (BPA) have been reported in human cells (E-screen assays) and in (italic)in vivo(/italic) studies of rodents, although the latter reports remain controversial, as do the exposure levels and adverse health effects of BPA in humans. In this study we report on an analytical high-performance liquid chromatography/fluorescence method for BPA and its conjugate in human urine and on the application of this method in two student cohorts. Urine, along with information on smoking, alcohol intake, and coffee/tea consumption, was collected in two different years from two different groups of university students, 50 in 1992 and 56 in 1999. Overall, the urinary BPA levels in the students in 1992 were significantly higher than were those in 1999. The BPA levels were also positively correlated with coffee and tea consumption in the 1992 cohort but not in the 1999 cohort. We speculate that recent changes made in Japan regarding the interior coating of cans used to package these beverages may partly explain these findings.

Aldehyde dehydrogenases (ALDHs) belong to a superfamily of NAD(P) + -dependent enzymes, which catalyze the oxidation of endogenous and exogenous aldehydes to their corresponding acids. Increased expression and/or activity of ALDHs, particularly ALDH1A1, have been reported to occur in human cancers. It is proposed that the metabolic function of ALDH1A1 confers the "stemness" properties to normal and cancer stem cells. Nevertheless, the identity of ALDH isozymes that contribute to the enhanced ALDH activity in specific types of human cancers remains to be elucidated. ALDH1B1 is a mitochondrial ALDH that metabolizes a wide range of aldehyde substrates including acetaldehyde and products of lipid peroxidation (LPO). In the present study, we immunohistochemically examined the expression profile of ALDH1A1 and ALDH1B1 in human adenocarcinomas of colon (N=40), lung (N=30), breast (N=33) and ovary (N=33) using an NIH tissue array. The immunohistochemical expression of ALDH1A1 or ALDH1B1 in tumor tissues was scored by their intensity (scale = 1-3) and extensiveness (% of total cancer cells). Herein we report a 5.6-fold higher expression score for ALDH1B1 in cancerous tissues than that for ALDH1A1. Remarkably, 39 out of 40 colonic cancer specimens were positive for ALDH1B1 with a staining intensity of 2.8 ± 0.5. Our study demonstrates that ALDH1B1 is more profoundly expressed in the adenocarcinomas examined in this study relative to ALDH1A1 and that ALDH1B1 is dramatically upregulated in human colonic adenocarcinoma, making it a potential biomarker for human colon cancer.

N2-ethylidene-2'-deoxyguanosine (N2-ethylidene-dG) is a major DNA adduct induced by acetaldehyde. Although it is unstable in the nucleoside form, it is relatively stable when present in DNA. In this study, we analyzed three acetaldehyde-derived DNA adducts, N2-ethylidene-dG, N2-ethyl-2'-deoxyguanosine (N2-Et-dG) and alpha-methyl-gamma-hydroxy-1,N2-propano-2'-deoxyguanosine (alpha-Me-gamma-OH-PdG) in the liver DNA of aldehyde dehydrogenase (Aldh)-2-knockout mice to determine the influence of alcohol consumption and the Aldh2 genotype on the levels of DNA damage. In control Aldh2+/+ mice, the level of N2-ethylidene-dG adduct in liver DNA was 1.9 +/- 0.7 adducts per 10(7) bases and was not significantly different than that of Aldh2+/- and -/- mice. In alcohol-fed mice (20% ethanol for 5 weeks), the adduct levels of Aldh2+/+, +/- and -/- mice were 7.9 +/- 1.8, 23.3 +/- 4.0 and 79.9 +/- 14.2 adducts per 10(7) bases, respectively, and indicated that adduct level was alcohol and Aldh2 genotype dependent. In contrast, an alcohol- or Aldh2 genotype-dependent increase was not observed for alpha-Me-gamma-OH-PdG, and N2-Et-dG was not detected in any of the analyzed samples. In conclusion, the risk of formation of N2-ethylidene-dG in model animal liver in vivo is significantly higher in the Aldh2-deficient population and these results may contribute to our understanding of in vivo adduct formation in humans.

Aldehyde dehydrogenase 3A1 (ALDH3A1), an ALDH superfamily member, catalyzes the oxidation of reactive aldehydes, highly toxic components of cigarette smoke (CS). Even so, the role of ALDH3A1 in CS-induced cytotoxicity and DNA damage has not been examined. Among all of the ALDH superfamily members, ALDH3A1 mRNA levels showed the greatest induction in response to CS extract (CSE) exposure of primary human bronchial epithelial cells (HBECs). ALDH3A1 protein accumulation was accompanied by increased ALDH enzymatic activity in CSE-exposed immortalized HBECs. The effects of overexpression or suppression of ALDH3A1 on CSE-induced cytotoxicity and DNA damage (γH2AX) were evaluated in cultured immortalized HBECs. Enforced expression of ALDH3A1 attenuated cytotoxicity and downregulated γH2AX. siRNA-mediated suppression of ALDH3A1 blocked ALDH enzymatic activity and augmented cytotoxicity in CSE-exposed cells. Our results suggest that the availability of ALDH3A1 is important for cell survival against CSE in HBECs.

Aldehyde dehydrogenase (ALDH) 2 plays a major role in the detoxification of aldehyde and is known to be responsible for alcohol preference. A diminished enzyme activity due to mutation of the Aldh2 gene is associated with high alcohol sensitivity and a low alcohol tolerance in humans. The genomic background distinguishing an alcohol preference and avoidance in various inbred mouse strains is not clear. We created Aldh2-negative mice by transgenic knockout of the Aldh2 gene into the high alcohol preference C57BL/6 background. The Aldh2 gene targeting (Aldh-/-) mice exhibited an alcohol avoidance characteristic. After free-choice ethanol and water drinking, brain and liver acetaldehyde concentrations of Aldh2-/- mice were almost equal to those of wild-type (Aldh2+/+) mice although the Aldh2-/- mice drank less ethanol than the Aldh2+/+ mice. This result indicates that a direct effect of the Aldh2 genotype plays an important role on alcohol preference and acetaldehyde concentration in the brain is correlated with alcohol avoidance. This highlights the potential benefits of alcoholism and alcohol-related disease research in the animal model of ALDH2 alleles.