Heme oxygenase 1 protects ethanol-administered liver tissue in Aldh2 knockout mice

• HO-1 is highly expressed in Aldh2−/− mouse liver.
• CYP2E1 is highly expressed in Aldh2−/− mouse liver.
• HO-1 and CYP2E1 levels were positively correlated.
• GCLC, TXNRD1, and cytokines examined are not influenced by Aldh2 genotypes.

A genetic polymorphism of the aldehyde dehydrogenase 2 (​ALDH2) gene, ALDH2*2, encodes an enzymatically defective ALDH2 protein. Recent epidemiological studies suggest that possessing ALDH2*2 is a protective factor for liver tissue in healthy individuals, although these studies lack a mechanistic explanation. Our animal studies have shown the same trend: levels of serum alanine transaminase (ALT), hepatic malondialdehyde (MDA), and hepatic tumor necrosis factor alpha (TNF-α) were lower in Aldh2 knockout (Aldh2−/−) mice than in wild-type (Aldh2+/+) mice after ethanol administration. To propose a mechanistic hypothesis, residual liver specimens from the previous experiment were analyzed. An anti-oxidative protein, heme oxygenase 1 (HO-1), and an oxidative stress-producing protein, cytochrome P450 2E1 (CYP2E1), were detected at higher levels in Aldh2−/− mice than in Aldh2+/+ mice, regardless of ethanol treatment. Other oxidative stress-related proteins and inflammatory cytokines did not show such a significant difference. To conclude, we propose a protective role of HO-1 in individuals with A​LDH2*2. Our continued studies support the epidemiological finding that possession of ALDH2*2 is a protective factor in the liver of the healthy individual.

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