Differential inhibition of rat and human hepatic cytochrome P450 by Andrographis paniculata extract and andrographolide.
The inhibitory effect of Andrographis paniculata extract (APE) and andrographolide (AND), the most medicinally active phytochemical in the extract, on hepatic cytochrome P450s (CYPs) activities was examined using rat and human liver microsomes. For this purpose, CYP1A2-dependent ethoxyresorufin-O-deethylation, CYP2B1-dependent benzyloxyresorufin-O-dealkylation, CYP2B6-dependent bupropion hydroxylation, CYP2C-dependent tolbutamide hydroxylation, CYP2E1-dependent p-nitrophenol hydroxylation and CYP3A-dependent testosterone 6 beta-hydroxylation activities, were determined in the presence and absence of APE or AND (0-200 microM). APE inhibited ethoxyresorufin-O-deethylation activity in rat and human liver microsomes, with apparent Ki values of 8.85 and 24.46 microM, respectively. In each case, the mode of inhibition was noncompetitive. APE also inhibited tolbutamide hydroxylation both in rat and human microsomes with apparent Ki values of 8.21 and 7.51 microM, respectively and the mode of inhibition was mixed type. In addition, APE showed a competitive inhibition only on CYP3A4 in human microsomes with Ki of 25.43 microM. AND was found to be a weak inhibitor of rat CYP2E1 with a Ki of 61.1 microM but did not affect human CYP2E1. In conclusion, it cannot be excluded from the present study that APE could cause drug-drug interactions in humans through CYP3A and 2C9 inhibition.
Laboratoire de Toxicologie Cellulaire, EA 3921 Optimisation Métabolique et Cellulaire, UFR des Sciences Médicales et Pharmaceutiques, Besançon, France.
D
D
Pekthong
H
H
Martin
C
C
Abadie
A
A
Bonet
B
B
Heyd
G
G
Mantion
L
L
Richert
D000328:Adult; D000368:Aged; D035685:Andrographis / Q000737:chemistry*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D004224:Diterpenes / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D008875:Middle Aged; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity
D004224:Diterpenes; D004791:Enzyme Inhibitors; C030419:andrographolide; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C507848:CYP2C9 protein, rat; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A