Metabolism of ginger component [6]‐shogaol in liver microsomes from mouse, rat, dog, monkey, and human

Abstract

[6]‐Shogaol, a major bioactive component of ginger, has been reported to have potent anti‐cancer activity. The in vitro metabolism of [6]‐shogaol was compared among five species with respect to metabolic profiles using liver microsomes from mouse (MLM), rat (RLM), dog (DLM), monkey (CyLM), and human (HLM). Following incubations with [6]‐shogaol, major reductive metabolites 1‐(4′‐hydroxy‐3′‐methoxyphenyl)‐4‐decen‐3‐ol (M6), 1‐(4′‐hydroxy‐3′‐methoxyphenyl)‐decan‐3‐ol (M9), and 1‐(4′‐ hydroxy‐3′‐methoxyphenyl)‐decan‐3‐one (M11) were found in all species. Two new oxidized metabolites of 6‐shogaol, M14 and M15, were identified as (1E,4E)‐1‐(4‐Hydroxy‐3‐ methoxyphenyl)deca‐1,4‐dien‐3‐one and (E)‐1‐(4‐Hydroxy‐3‐ methoxyphenyl)dec‐1‐en‐3‐one, respectively. The kinetic parameters of M6 in liver microsomes from each respective species were quantified using Michaelis‐Menton theory. A broad CYP450 inhibitor, 1‐aminobenzotriazole (ABT), precluded formation of oxidative metabolites M14 and M15 in HLM, and diminished oxidative metabolism in MLM, RLM, DLM, and CyLM. Additionally, 18β‐glycyrrhetinic acid, an aldo‐keto reductase (AKR) inhibitor, eradicated the formation of the reductive metabolites M6, M9, and M11 in all species. Metabolites M14 and M15 were tested for cancer cell growth inhibition and induction of apoptosis and both showed substantial activity, with M14 displaying greater potency than [6]‐shogaol.We conclude that [6]‐shogaol is metabolized extensively in mammalian species mouse, rat, dog, monkey, and human, and that there are significant interspecies differences to consider when planning pre‐clinical trials towards [6]‐shogaol chemoprevention.This work was supported by NIH grants CA138277 and CA138277S1 to S. Sang.