Induction of cytochrome P450 enzymes in rat liver by two conazoles, myclobutanil and triadimefon.
This study was undertaken to examine the inductive effects of two triazole antifungal agents, myclobutanil and triadimefon, on the expression of hepatic cytochrome P450 (CYP) genes and on the activities of CYP enzymes in male Sprague Dawley rats. Rats were dosed with the conazoles at three dose levels by gavage for 14 days: myclobutanil (150, 75, and 10mgkg(-1) body weight day(-1); triadimefon (115, 50, and 10 mg kg(-1) body weight day-'), which included their maximum tolerated dose levels (MTD). Both myclobutanil and triadimefon significantly induced pentoxyresorufin O-depentylase activities at their MTD levels: myclobutanil, 8.1-fold at 150mgkg(-1) body weight day- ; and triadimefon, 18.5-fold at 115mgkg(-1) body weight day-'. Benzyloxyresorufin O-debenzylase activities were similarly increased: myclobutanil, 13.3-fold; triadimefon, 27.7-fold. Quantitative real-time reverse-transcription polymerase chain reaction assays were used to characterize the mRNA expression of specific CYP genes induced by these two conazoles. Myclobutanil and triadimefon treatment at their MTD levels significantly increased rat hepatic mRNA expression of CYP2B1 (14.3- and 54.6-fold), CYP3A23/3A1 (2.2- and 7.3-fold), and CYP3A2 (1.5- and 1.7-fold). Western immunoblots of rat hepatic microsomal proteins identified significantly increased levels of CYP isoforms after myclobutanil or triadimefon treatment at their MTD levels: CYP2BI/2 (4.8- and 5.3-fold), and CYP3A1 (2.2- and 2.9-fold). Triadimefon also increased CYP3A2 immunoreactive protein levels 1.8-fold. These results indicate that triadimefon and myclobutanil, like other triazole-containing conazoles, induced CYP2B and CYP3A families of cytochromes in rat liver.
Sun
G
G
National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Grindstaff
R D
RD
Thai
S F
SF
Lambert
G R
GR
Tully
D B
DB
Dix
D J
DJ
Nesnow
S
S
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D001483:Base Sequence; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis / Q000235:genetics; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology*; D009570:Nitriles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D014230:Triazoles / Q000494:pharmacology*
D000935:Antifungal Agents; D017931:DNA Primers; D008565:Membrane Proteins; D009570:Nitriles; D012333:RNA, Messenger; D014230:Triazoles; C032910:triadimefon; D003577:Cytochrome P-450 Enzyme System; C446685:systhane; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; C025619:steroid 16-beta-hydroxylase