Toxicological profiling and diuretic potential of arbutin via aldosterone synthase gene inhibition

Arbutin (ARB), a natural polyphenol isolated from the bearberry plant Arctostaphylos uva-ursi, has been studied for its diverse pharmacological activities including anti-diabetic, cardioprotective and anti-inflammatory effects. This study aimed to evaluate arbutin's diuretic activity, focusing on its impact on aldosterone synthase gene expression and its toxicity profile.

Acute toxicity was assessed using single doses ranging from 500 to 9000 mg/kg and sub-acute toxicity with doses of 375 and 750 mg/kg over 14 days. To evaluate acute diuretic activity, ARB was administered in three doses (25, 50 and 75 mg/kg i.p) alongside standard groups, furosemide (FUR) 10 mg/kg i.p and Spironolactone (SPIR) 25 mg/kg i.p. In sub-acute diuretic study, treatment was administered for seven days, followed by blood collection and adrenal dissection for gene expression analysis.

Acute toxicity studies revealed that ARB is well-tolerated up to 7000 mg/kg with no significant changes in organ and body weight. However, sub-acute studies showed minor changes in leukocyte count, alkaline phosphatase (ALP), alanine aminotransferase (ALT) and triglycerides (TGs) at high doses while histopathological evaluations revealed no severe organ damage. The diuretic index and electrolyte analysis confirmed the potential of ARB as diuretic and saluretic with reduced risk of hyperuricemia and hyperkalemia. Gene expression studies showed non-selective downregulation of aldosterone synthase gene (CYP11B2) and 11β-hydroxylase (CYP11B1). While the effects on 17α-hydroxylase (CYP17A1) were less pronounced than SPIR, indicating fewer possible anti-androgenic effects.

Our findings suggest that ARB is a promising diuretic agent with a favorable safety profile.