Luteolin-7-methylether from Leonurus japonicus inhibits estrogen biosynthesis in human ovarian granulosa cells by suppression of aromatase (CYP19).

Leonurus japonicus (motherwort) has been widely used to treat gynecological disorders, in which estrogen is often dysregulated, for a long time in China and other Asian countries. However, the chemical constituents and mechanisms underlying the activity of this medicinal plant are not fully understood. Seventeen of forty-six tested natural products from L. japonicus showed stimulatory or inhibitory effects on estrogen biosynthesis with different potency in human ovarian granulosa-like KGN cells. Luteolin-7-methylether (XLY29) potently inhibited 17β-estradiol production (IC₅₀: 5.213 μM) by decreasing the expression of aromatase, the only enzyme in vertebrates that catalyzes the biosynthesis of estrogens, but had no effect on the catalytic activity of aromatase. XLY29 decreased the expression of aromatase promoter I.3/II, and suppressed the phosphorylation of cAMP response element-binding protein. XLY29 potently inhibited phosphorylation of p38 mitogen-activated protein kinase and AKT but had no effect on phosphorylation of extracellular signal-regulated kinase and c-Jun N-terminal kinase. XLY29 also decreased the serum 17β-estradiol level and disturbed estrous cycle in mice. These results suggest that modulation of estrogen biosynthesis is a novel effect of L. japonicus, and XLY29 warrants further investigation as a new therapeutic means for the treatment of estrogen-related diseases.