Neonatal hyperoxia and cytochrome P450 imprinting in adulthood.
We hypothesized that during a critical neonatal period hyperoxia may produce alterations of sex-specific cytochrome P450 isozymes in adulthood (enzyme imprinting). To test this, newborn rats were exposed to 24 or 72 h of hyperoxia (O2 > 95%) within 24 h after birth and killed at 120 d. In males, significant negative imprinting (decrease) was found in total cytochrome P450 content and male-specific CYP2C11 in the hyperoxia groups. Positive imprinting (increase) was noted in CYP1A2 and male-specific CYP3A2 in the 72-h hyperoxia group. These alterations were essentially similar when expressed on a per microsomal protein or per liver basis. In addition, the level of hepatic glucocorticoid receptor in adult male rats was elevated after neonatal hyperoxia. In females, there was a significant body and liver weight loss after hyperoxic exposure, which resulted in a negative imprinting of CYP1A2 and female-specific 2C12 in the 72-h hyperoxia group on a per liver basis, whereas the measured parameters were unaltered when expressed per microsome. In general, the changes were more marked with longer hyperoxic exposure, suggesting that more pronounced alterations may be induced with prolonged neonatal hyperoxia. Because hyperoxic exposure in premature neonates is a common clinical practice and decreased CYP2C11 in adult males is expected to result in feminization, we believe that the scope of this work should be expanded and eventually tested for its relevance in human subjects.
Kikkawa
Y
Y
Department of Pathology, College of Medicine, University of California at Irvine 92717.
Fujita
I
I
Sindhu
R K
RK
D000818:Animals; D000831:Animals, Newborn; D001189:Aryl Hydrocarbon Hydroxylases; D001835:Body Weight / Q000187:drug effects; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D003580:Cytochromes; D005260:Female; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D008565:Membrane Proteins; D009929:Organ Size / Q000187:drug effects; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010100:Oxygen / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism; D012727:Sex Characteristics; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000378:metabolism
D003580:Cytochromes; D008565:Membrane Proteins; D011965:Receptors, Glucocorticoid; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C017170:Cyp1a2 protein, rat; C465260:Cyp3a2 protein, rat; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; C022657:steroid hormone 6-beta-hydroxylase; D010089:Oxidoreductases, N-Demethylating; D010100:Oxygen