Regulation of constitutive mouse hepatic cytochromes P450 and growth hormone signaling components by 3-methylcholanthrene.
3-Methylcholanthrene (MC) activates the aryl hydrocarbon receptor and increases expression of cytochrome P450 (P450) enzymes such as CYP1A1. MC also decreases expression of CYP2C11, the major hepatic P450 in male rats that is regulated by pulsatile growth hormone (GH) secretion via a pathway partially dependent on signal transducer and activator of transcription 5b (STAT5b). If disruption of this GH signaling pathway is important for MC's ability to suppress CYP2C11 transcription, we hypothesize that MC suppresses other male-specific genes (e.g., mouse Cyp2d9) regulated by pulsatile GH with STAT5b dependence. We examined the time course of MC's effects on hepatic P450s and GH signaling components in male C57BL/6 mice. P450 content, heme content, and NADPH P450 oxidoreductase activity were induced 2.3-, 1.8-, and 1.3-fold, respectively, by MC. MC dramatically induced CYP1A1 mRNA, protein, and catalytic activity. MC caused a 42% decrease in CYP2D9 protein, a 28% decrease in CYP2D9 mRNA, and a 27% decrease in testosterone 16alpha-hydroxylation activity. MC caused a pronounced decrease in CYP3A protein; however, there was no apparent change in testosterone 6beta-hydroxylation activity, and changes in mRNA levels for CYP3A forms were relatively small. Expression of GH receptor and major urinary protein 2, a gene regulated by GH with STAT5b dependence, was decreased by MC at the mRNA level. These results show that MC suppresses mouse Cyp2d9, a pulsatile GH- and STAT5b-dependent male-specific gene, via a pretranslational mechanism that may involve disrupted GH signaling. Mouse CYP3A protein levels are dramatically decreased by MC via a mechanism that is not yet understood.
Lee
Chunja
C
Department of Pharmacology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada.
Hutson
Janine R
JR
Tzau
Vivien Kok-Fung
VK
Riddick
David S
DS
D000818:Animals; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D013006:Growth Hormone / Q000378:metabolism*; D006900:Hydroxylation; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000235:genetics / Q000378:metabolism; D012737:Sex Factors; D015398:Signal Transduction; D013739:Testosterone / Q000378:metabolism; D013997:Time Factors; D008565:Membrane Proteins
D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D000072467:Cytochrome P450 Family 2; D013006:Growth Hormone; D008748:Methylcholanthrene; D011506:Proteins; D012333:RNA, Messenger; D011986:Receptors, Somatotropin; D013739:Testosterone; C035737:major urinary proteins; C504575:CYP2D9 protein, mouse; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins