Effect of Chrysin and Natural Coumarins on UGT1A1 and 1A6 Activities in Rat and Human Hepatocytes in Primary Culture

Abstract

Flavonoids and coumarins are naturally occurring compounds that are widely distributed in vegetables and have a broad pharmacological activity. Inducibility of UDP-glucuronosyltransferases (UGTs) by xenobiotics is well documented and can be considered beneficial for health. In particular, UGT1A1-dependent bilirubin conjugation plays a critical role in the detoxification of neurotoxic bilirubin and phenobarbital-mediated UGT1A1 induction therapy is commonly used in the treatment of unconjugated hyperbilirubinemic diseases such as Crigler-Najjar type II disease. In the present study, the effects of the flavone chrysin and six natural coumarins isolated from various Rutaceous plants on UGT1A6-dependent P-nitrophenol and/or UGT1A1-dependent bilirubin glucuronoconjugation activities were evaluated in cultured rat and human hepatocytes and compared to those of the prototypical UGT1A inducers beta-naphthoflavone, phenobarbital and clofibric acid. After 3 days of treatment at a concentration of 25 microM, the pyranocoumarins avicennin and CIS-avicennol, and the furocoumarins bergapten and imperatorin, increased by 2-fold UGT1A1-dependent activity, equivalent to the increases obtained with chrysin at 25 microM, whereas in the presence of the simple coumarins such as coumarin or umbelliferone, UGT1A1-dependent activity was not modified. In terms of structural requirements for UGT1A1 induction, the present study suggests that the B-ring (phenyl) for chrysin and the furan or pyran rings for coumarins are essential for the biological activity.

Antioxidative and antigenotoxic properties of vegetables and dietary phytochemicals: The value of genomics biomarkers in molecular epidemiology

“…The importance of investigating such a potential health concern is even more evident in view of the fact that the intake of high doses of purified NAhRAs is being promoted as healthy food supplements. The interest in this type of food supplements is based on the observation that some identified NAhRAs from vegetables and fruits, like indole‐3‐carbinol in cruciferous vegetables, furocoumarins in citrus fruits and flavonoids such as chrysin, baicalein and cantharidin in vegetables and herbs can show health‐promoting effects, especially as tumor suppressors and are thought to be an important cause for the observed beneficial effects of vegetable‐ and fruit‐enriched diets 3, 61–63. It is remarkable that the proposed mechanism of anti‐tumor activity is also based on the AhR activation, and the subsequent induction of phase I and II biotransformation enzymes like CYP1A1 , CYP1A2 and UDPGT1A6 64, 65.…”

The antiplasmodium effects of a traditional South American remedy: Zanthoxylum chiloperone var. angustifolium against chloroquine resistant and chloroquine sensitive strains of Plasmodium falciparum

“…To date, there is a paucity of research on the biological activity of avicennol, which has been previously identified in Z. elephantiasis Macfad (Gray et al, 1977). Recent work with avicennol reports an induction of UDP-glucuronosyltransferases (UGT), specifically UGT1A1, which detoxifies xenobiotics (Chlouchi et al, 2007).…”

Metabolic Changes of Aflatoxin B1 to become an Active Carcinogen and the Control of this Toxin

“…BNF is an inducer of various detoxification enzymes, such as CYPs 450 and uridine-5'-diphosphoglucuronosyltransferases (UGTs) [167].…”