In vitro determination of the effect of Andrographis paniculata extracts and andrographolide on human hepatic cytochrome P450 activities

Abstract

We investigated the effects of Andrographis paniculata (AP) extracts and andrographolide on the catalytic activity of three human cDNA-expressed cytochrome P450 enzymes: CYP2C9, CYP2D6 and CYP3A4. In vitro probe-based high performance liquid chromatography assays were developed to determine CYP2C9-dependent tolbutamide methylhydroxylation, CYP2D6-dependent dextromethorphan O-demethylation and CYP3A4-dependent testosterone 6β-hydroxylation activities in the presence and absence of AP extracts and andrographolide. Our results indicate that AP ethanol and methanol extracts inhibited CYP activities more potently than aqueous and hexane extracts across the three isoforms. Potent inhibitory effects were observed on CYP3A4 and CYP2C9 activities (K (i) values below 20 μg/ml). Andrographolide was found to exclusively but weakly inhibit CYP3A4 activity. In conclusion, data presented in this study suggest that AP extracts have the potential to inhibit CYP isoforms in vitro. There was, however, variation in the potency of inhibition depending on the extracts and the isoforms investigated.

In Vitro Assessment of 36 CYP2C9 Allelic Isoforms Found in the Chinese Population on the Metabolism of Glimepiride

“…However, almost all of them only focused on two commonly investigated alleles, *2 and *3, in relatively small sample sizes [22,[28][29][30][31][32][33][34][35][36][37]. Only two groups focused their attention on other alleles; one group found a new allele *13 [38], while the other group detected the three rare alleles *8, *11 and *31 [22].…”

Interactions between antidiabetic drugs and herbs: an overview of mechanisms of action and clinical implications

“…Potentially additive pharmacological effects are apparent with the use of the herb in combination with antidiabetic medications as the herb has been shown to lead to enhanced uptake of radioactive glucose in the isolated soleus muscle of STZ-diabetic rats in a concentration-dependent manner [83]. Although there are no studies examining interactions between Andrographis paniculata and antidiabetic drugs, Andrographis paniculata has been shown to inhibit CYP2C19 activity [84] for which the antidiabetic drugs such as glibenclamide, glimepiride, glipizide, nateglinide, rosiglitazone, pioglitazone, repaglinideare substrates, thereby suggesting that there is the potential adverse outcomes as a result of an increase in plasma concentrations of these medications and subsequent enhanced glucose lowering effect, although this theory remains to be confirmed.…”

Hepatoprotective Diterpenoids Isolated from <i>Andrographis paniculata</i>

“…A. paniculata ethanol and methanol extracts inhibited CYP3A4 and CYP2C9 activities more than aqueous and hexane extracts. On the other hand, andrographolide was found to weakly inhibit CYP3A4 activity [38]. Molecular docking analysis data supported that andrographolide and 14-deoxy-11,12didehydroandrographolide induced CYP1A1 expression or co-treatment with CYP1A1 inducer (-naphthoflavone, BNF) showed a synergistic increase expression of CYP1A1.…”

“…A. paniculata extract ↑ mouse hepatic CYP1A1 and CYP2B [31] Andrographolide ↑ CYP1A1 and CYP1A2 mRNA expression levels [32] Andrographolide ↑ CYP1A1 and CYP1B1 mRNA expression [33] A. paniculata 60% ethanol extract or andrographolide ↓ CYP3A, CYP2C9 in vitro and CYP2C11 in vivo [34,35] Andrographolide plus 3-MC synergistically ↑ CYP1 family gene in male B6 mice [36] 14-deoxy-11,12-didehydroandrographolide and andrographolide ↓ CYP1A2, CYP2D6 and CYP3A4 expression in HepG2 cells [37] A. paniculata ethanol and methanol extracts ↓ CYP3A4, CYP2C9; andrographolide ↓ CYP3A4 [38] Andrographolide and 14-deoxy-11,12-didehydroandrographolide co-treatment with BNF ↑ CYP1A1 expression; but, neoandrographolide co-treatment with BNF ↓ CYP1A1 expression [39] Andrographolide (1, 10, 100 M) ↓ CYP3A4 mRNA and protein levels in Caco-2 cells [40] 3. Modulate GSH content…”