Differential in vivo effects of alpha-naphthoflavone and beta-naphthoflavone on CYP1A1 and CYP2E1 in rat liver, lung, heart, and kidney.
Male Sprague-Dawley rats were treated intraperitoneally with corn oil, the aryl hydrocarbon receptor (AHR) agonist beta-naphthoflavone (betaNF), or the relatively weak AHR agonist alpha-naphthoflavone (alphaNF). Animals treated with betaNF experienced a significant loss (12%) of total body mass over 5 days and a dramatic elevation of CYP1A1 mRNA in all of the organs studied. Treatment with alphaNF had no significant effect on body mass after 5 days and caused only minor increases of liver, kidney, and heart CYP1A1 mRNA. In contrast, lung CYP1A1 mRNA was increased by alphaNF treatment to levels comparable to that seen with betaNF treatment. CYP2E1 mRNA levels were also elevated in liver, lung, kidney, and heart in response to betaNF treatment, whereas alphaNF was without effect. Large increases of CYP1Al-dependent 7-ethoxyresorufin O-deethylation (EROD) activity occurred with microsomes prepared from the tissues of betaNF-treated animals. Comparatively small changes were associated with alphaNF treatment, with the exception of lung, where EROD activity was increased to approximately 60% of that with betaNF treatment. CYP2E1-dependent p-nitrophenol hydroxylase (PNP) activity was also increased by betaNF treatment in microsomes prepared from kidney (3.1-fold), whereas alphaNF was without effect. In contrast, alphaNF or betaNF treatment caused significant decreases of lung microsomal PNP (72% and 27% of corn oil control, respectively) and 7-pentoxyresorufin O-deethylation (48% and 17% of corn oil control, respectively) activities, indicating that PNP activity may be catalyzed by P450 isoforms other than CYP2E1 in rat lung. We conclude that betaNF and alphaNF have differential effects on the expression and catalytic activity of CYP1A1 and CYP2E1, depending upon the organ studied. These changes most likely occur as a result of the direct actions of these compounds as AHR agonists, in addition to secondary effects associated with AHR-mediated toxicity.
Sinal
C J
CJ
Department of Pharmacology and Toxicology, University of Western Ontario, London, Canada.
Webb
C D
CD
Bend
J R
JR
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000235:genetics*; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008168:Lung / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008861:Microsomes / Q000201:enzymology*; D008862:Microsomes, Liver / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology*; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects*; D019324:beta-Naphthoflavone / Q000494:pharmacology*
D001571:Benzoflavones; D012333:RNA, Messenger; C011512:alpha-naphthoflavone; D019324:beta-Naphthoflavone; D019392:Cytochrome P-450 CYP2E1; D019363:Cytochrome P-450 CYP1A1