In vitro induction of cytochrome P4503A1-mRNA and testosterone hydroxylation in precision-cut liver slices from male and female rats.
Cytochrome P450 (CYP) 3A is constitutively highly expressed in the liver. Thus detection of induction might be more difficult than shown for scarcely expressed CYP families. In this paper the suitability of rat liver slices to prove CYP3A inducibility was demonstrated. CYP3A dependent basal testosterone hydroxylation (TH) at positions 15beta, 6beta and 2beta was lower in liver slices from female than male rats, but was more markedly induced by 10(-6) M dexamethasone (DEX) within 24 h (mean induction factors 12.5, 18.3 and 140, respectively, for female slices and 3.7, 2.3 and 3.5, respectively, for male slices). Basal expression of CYP3A1-mRNA was stable in vitro until 24 h and did not differ between male and female rats. In liver slices from male rats this mRNA was induced about 14 fold by both DEX and pregnenolone 16alpha-carbonitrile (PCN) within 24 h. In one sample of a female rat a similar range of CYP3A1-mRNA induction was reached by DEX. Altogether, CYP3A induction can be detected more sensitively in liver slices from female than male rats, if TH rates are used as indicators. With liver slices from male rats CYP3A1-mRNA reacts more sensitively to inducers than TH.
Glöckner
Reinhild
R
Institute of Pharmacology and Toxicology, Friedrich Schiller University Jena, Germany. rglo@mti-n.uni-jena.de
Wagener
Juliane
J
Lieder
Angelika
A
Müller
Dieter
D
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis* / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006900:Hydroxylation; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009924:Organ Culture Techniques; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012737:Sex Factors; D013739:Testosterone / Q000378:metabolism*
D012333:RNA, Messenger; D011285:Pregnenolone Carbonitrile; D013739:Testosterone; D003907:Dexamethasone; D001189:Aryl Hydrocarbon Hydroxylases; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A