Formation of hepatic DNA adducts by methyleugenol in mouse models: drastic decrease by Sult1a1 knockout and strong
Kristin Herrmann1, Wolfram Engst, Walter Meinl
1Department of Nutritional Toxicology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, 14558 Nuthetal, Germany.
Carcinogenesis
|December 10, 2013
Summary
Methyleugenol forms DNA adducts, linked to cancer, via sulfotransferase (SULT) enzymes. Human SULT1A1/2 are more potent activators than mouse Sult1a1, with low doses forming adducts in humanized mice.
Area of Science:
- Toxicology
- Carcinogenesis
- Enzymology
Background:
- Methyleugenol, a natural compound in herbs and spices, is a known hepatocarcinogen in rodents.
- It can form DNA adducts through side-chain hydroxylation and sulfation.
- Previous studies showed human sulfotransferases (SULTs) 1A1/1A2 and mouse Sult1a1 activate methyleugenol metabolites into mutagens.
Purpose of the Study:
- To investigate the in vivo role of SULT enzymes in hepatic DNA adduct formation by methyleugenol in mice.
- To compare the activity of mouse Sult1a1 and human SULT1A1/2 in methyleugenol activation.
- To assess the formation of DNA adducts at low, human-relevant doses of methyleugenol.
Main Methods:
- Utilized FVB/N mice: wild-type (wt), Sult1a1 knockout (ko), transgenic for human SULT1A1/2 (tg), and combined ko-tg strains.
- Administered methyleugenol (50mg/kg) and 1'-hydroxymethyleugenol (1'-OH-ME) to mice.
- Quantified N(2)-(trans-methylisoeugenol-3'-yl)-2'-deoxyguanosine and N(6)-(trans-methylisoeugenol-3'-yl)-2'-deoxyadenosine adducts in liver DNA.
Main Results:
- Adduct formation by methyleugenol and 1'-OH-ME was highly dependent on SULT1A enzyme presence.
- Human SULT1A1/2 in tg and ko-tg mice showed significantly higher adduct levels than mouse Sult1a1 in wt and ko mice.
- A low dose of methyleugenol (0.05 mg/kg) formed detectable adducts in humanized (ko-tg) mice.
- 3'-hydroxymethylisoeugenol (3'-OH-MIE) formed minimal hepatic adducts compared to 1'-OH-ME, suggesting in vivo detoxification.
Conclusions:
- SULT1A enzymes are critical for methyleugenol-induced hepatic DNA adduct formation in vivo.
- Human SULT1A1/2 exhibit greater potency than mouse Sult1a1 in this activation pathway.
- Low-level methyleugenol exposure can lead to DNA adduct formation in individuals with human SULT1A activity, highlighting potential human health risks.
