In vitro assessment of P450 induction potential of novel chemopreventive agents SR13668, 9-cis-UAB30, and pentamethychromanol in primary cultures of human hepatocytes.
Several compounds, including 2,10-dicarbethoxy-6-methoxy-5,7-dihydroindolo[2,3-b]carbazole (SR13668), (2E,4E,6Z,8E)-8-(3',4'-dihydro-1'(2'H)-napthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid (9-cis-UAB30), and 2,2,5,7,8-pentamethyl-6-chromanol (PMCol), were selected as promising chemopreventive agents and have entered preclinical trials for cancer prevention. The potential for adverse drug events resulting from interactions with other administered drugs, food components, or food additives presents an important question. Among the most important drug-drug interactions (DDI) is the potential of a new chemical entity (NCE) to induce cytochrome P450 enzymes (P450). Drug induction of P450 enzymes can lead to adverse drug interactions by increasing the metabolism of other drugs that are substrates for the induced isoform. Currently, sandwich cultured primary human hepatocytes are the standard for predicting human P450 enzyme induction in vitro as these cells retain the ability to respond to prototypical P450 inducers with the same specificity and potency exhibited in vivo. Therefore, a select panel of inducible P450 target genes (CYP1A2, CYP2B6, and CYP3A4) and their induction activity (measured by LC-MS/MS of respective marker substrate metabolites) were monitored in cultured hepatocytes following treatment with SR13668, 9-cis-UAB30, or PMCol to predict clinically significant drug-induced expression. The concentration ranges of the NCE used were selected to maximize the clinical relevance of these results. All responses were evaluated according to major prototypical P450 inducers (i.e., 3-methylcholanthrene, 3-MC; phenobarbital, PB; rifampicin, RIF) and increases > or = 40% of the respective positive control(s) were considered an indication of demonstrable induction. Herein, we report that there is low potential for DDI with SR13668 and PMCol due to enzyme induction of CYP1A2, CYP2B6, and CYP3A4 expression at the concentrations examined. Similarly, the study results suggested that 9-cis-UAB30 has low potential to induce CYP1A2 and CYP3A4 expression at the concentrations examined. However, 9-cis-UAB30 was shown to significantly induce CYP2B6 enzyme activity at 10 microM suggesting the potential for DDI as a result.
Jackson
Jonathan P
JP
CellzDirect/Invitrogen Corporation, Austin, TX 78754, United States.
Kabirov
Kasim K
KK
Kapetanovic
Izet M
IM
Lyubimov
Alexander
A
D002227:Carbazoles / Q000494:pharmacology*; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004790:Enzyme Induction / Q000187:drug effects; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D009281:Naphthalenes / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
C048427:2,2,5,7,8-pentamethylchroman; D002227:Carbazoles; D002839:Chromans; D005231:Fatty Acids, Unsaturated; D009281:Naphthalenes; D012333:RNA, Messenger; C523402:SR 13668; D003577:Cytochrome P-450 Enzyme System; C112106:UAB 30