Lack of effect of methotrexate on the expression of constitutive hepatic cytochromes P450 in the male rat.
1. The effects of methotrexate (MTX) on the expression of selected constitutive cytochrome P450 (CYP) isozymes in the liver of male rats at the catalytic activity and mRNA levels were examined. 2. Male rats received a single intraperitoneal injection of MTX (4 mg/kg) or vehicle and were killed, 1, 2, 7 or 14 days following drug administration. 3. Hepatic microsomes were used for determination of total CYP content, NADPH-CYP reductase activity, aminopyrine N-demethylase activity, and androstenedione (AD) hydroxylation activity; total RNA was also isolated from liver and was used for hybridization analysis of CYP isozyme expression at the mRNA level. 4. MTX did not affect any of the following parameters at any time-point in comparison with the corresponding vehicle control: body weight, liver weight, hepatic microsomal protein content, total CYP content, NADPH-CYP reductase activity, aminopyrine N-demethylase activity, AD 6 beta- and 7 alpha-hydroxylase activity, and CYP3A2 mRNA content. 5. The major male-specific CYP isozyme, 2C11, was down-regulated by MTX treatment as revealed by a marginal (25%), but statistically significant decrease in AD 16 alpha-hydroxylase activity at day 14 and a marginal (18%), but statistically significant decrease in CYP2C11 mRNA content at day 14. 6. In comparison with other antineoplastic drugs that have been examined, MTX appears to possess a lesser capacity for modulation of hepatic CYP enzymes.
Cheung
R L
RL
Department of Pharmacology, University of Toronto, Ontario, Canada.
Lee
C
C
Jones
E J
EJ
Riddick
D S
DS
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001483:Base Sequence; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D008565:Membrane Proteins; D008727:Methotrexate / Q000494:pharmacology*; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000378:metabolism*
D008565:Membrane Proteins; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; C022657:steroid hormone 6-beta-hydroxylase; D008727:Methotrexate