Prenatal expression of N-acetyltransferases in C57Bl/6 mice.
Exposure to carcinogens such as 4-aminobiphenyl (4ABP), found in tobacco smoke and other combustion products, results in the formation of detectable levels of 4ABP-hemoglobin adducts in cord blood and 4ABP-DNA adducts in conceptal tissue. The presence of these adducts requires that the parent compound undergo biotransformation. When exposure occurs in utero, the maternal, placental and conceptal tissues are all possible sites for the formation of DNA-reactive products. One step in the activation of 4ABP is catalyzed by N-acetyltransferases (NAT). The expression of NAT was evaluated in gestational day (GD) 10-18 conceptal tissues from C57Bl/6 mice. There was a quantitative increase in NAT1 and NAT2 mRNAs with increasing gestational age that was also reflected in age-related changes in functional protein measured as 4ABP-NAT activity. The ability to acetylate 4ABP increased from GD10 to 18 and was lower in conceptal tissue than in adult liver. The potential toxicologic significance of prenatal NAT expression was assessed by formation of 4ABP-DNA adducts. At GD 15 and 18, 4ABP-DNA adducts were detected by immunohistochemistry 24 h following a single oral dose of 120 mg 4ABP/kg. Based on nuclear fluorescence, conceptual 4ABP-DNA adducts were present at similar levels at GD15 and 18. Levels of 4ABP-DNA adducts were significantly higher in maternal liver compared with the conceptus. Results from this study show that both NAT genes were expressed prenatally and that functional enzymes were present. These data support the possible in situ generation of reactive products by the conceptus. The relative contributions of maternal activation of 4ABP and that by the conceptus remain to be determined.
McQueen
Charlene A
CA
Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, PO Box 210207, Tucson, AZ 85721, USA. mcqueen@pharmacy.arizona.edu
Mitchell
M Kimberly
MK
Dang
Lanvi N
LN
Chau
Binh
B
Tjalkens
Ronald B
RB
Philbert
Martin A
MA
D000611:Aminobiphenyl Compounds / Q000633:toxicity; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D001483:Base Sequence; D002273:Carcinogens / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D017931:DNA Primers; D005260:Female; D007527:Isoenzymes / Q000235:genetics*; D008099:Liver / Q000196:embryology / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000611:Aminobiphenyl Compounds; D002273:Carcinogens; D017931:DNA Primers; D007527:Isoenzymes; D012333:RNA, Messenger; C006757:4-biphenylamine; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1