Effects of Garlic on Cytochromes P450 2C9- and 3A4-Mediated Drug Metabolism in Human Hepatocytes

Beatrice E. Ho

doi:10.3797/scipharm.1002-11

Abstract

Several reports suggest garlic supplements may inhibit the metabolism of cytochrome P450 (CYP) 2C9 and CYP3A4 substrates, such as warfarin and saquinavir. To characterize the effects of garlic extract on CYP2C9 and CYP3A4 enzyme activity immortalized human hepatocytes (Fa2N-4 cells) were exposed to garlic extract (0–200 μg/mL). CYP2C9 and CYP3A4 enzyme activities were evaluated in parallel with enzymatic activities, expression of respective RNA transcripts was also assessed.Exposure to increasing concentrations of garlic extract led to progressive reduction in Fa2N-4 CYP2C9 activity as detected by diclofenac hydroxylation. CYP2C9 mRNA expression also revealed a concentration-dependent reduction. Greater than 90% reduction in CYP2C9 activity was observed following four days of exposure to 50 μg/mL garlic extract. In contrast, exposure to garlic extract had no effect on the CYP3A4 enzymatic activity or RNA transcript concentration in Fa2N-4. Therefore, suppression of CYP2C9 expression and activity is a heretofore unrecognized mechanism by which garlic extract may modulate CYP activity. Exposure of hepatocytes to garlic extract may reduce the expression and activity of CYP2C9 with no detectible effects on CYP3A4.

Highlights

Garlic supplements are amongst the top ten best selling herbal supplements, which leads to concern over the reported garlic-drug interactions [1,2,3]
A human microsomal P450 activity study suggested that only two garlic constituents, S-allyl- or S-methyl-L-cysteine at 0.1 mg/mL significantly inhibited cytochrome P450 3A4 (CYP3A4) with no impact on cytochrome P450 2C9 (CYP2C9), CYP2C19 or CYP1A2 [10]
Rifampin successfully induced CYP2C9 and CYP3A4 activity and mRNA expression in the Fa2N-4 cells, which confirms the responsiveness of this immortalized cell line to cytochrome P450 (CYP) induction (Tables 1 and 2)

Summary

Introduction

Garlic supplements are amongst the top ten best selling herbal supplements, which leads to concern over the reported garlic-drug interactions [1,2,3]. We used the Fa2N-4 cells to evaluate the effects of garlic extract on the expression and activity of CYP2C9 and CYP3A4 in the cells. Rifampin successfully induced CYP2C9 and CYP3A4 activity and mRNA expression in the Fa2N-4 cells, which confirms the responsiveness of this immortalized cell line to CYP induction (Tables 1 and 2).

Results

Conclusion