Higher susceptibility to aflatoxin B(1)-related hepatocellular carcinoma in glycine N-methyltransferase knockout mice.
In both humans and rodents, males are known to be more susceptible than females to hepatocarcinogenesis. We have previously reported that glycine N-methyltransferase (GNMT) interacts with aflatoxin B(1) (AFB(1)) and reduces both AFB(1)-DNA adduct formation and hepatocellular carcinoma (HCC) in mice. We also reported that 50% of the males and 100% of the females in a small group of Gnmt null (Gnmt-/-) mice developed HCC, with first dysplastic hepatocellular nodules detected at mean ages of 17 and 16.5 months, respectively. In our study, we tested our hypothesis that male and female Gnmt-/- mice are susceptible to AFB(1) carcinogenesis, and that the absence of Gnmt expression may accelerate AFB(1)-induced liver tumorigenesis. We inoculated Gnmt-/- and wild-type mice intraperitoneally with AFB(1) at 7 days and 9 weeks of age and periodically examined them using ultrasound. Dysplastic hepatocellular nodules were detected in six of eight males and five of five females at 12.7 and 12 months of ages, respectively. Dysplastic hepatocellular nodules from 5/8 (62.5%) male and 4/5 (80%) female Gnmt-/- mice were diagnosed as having HCC, ∼6 months earlier than AFB(1)-treated wild-type mice. Results from microarray and real-time PCR analyses indicate that five detoxification pathway-related genes were downregulated in AFB(1)-treated Gnmt-/- mice: Cyp1a2, Cyp3a44, Cyp2d22, Gsta4 and Abca8a. In summary, we observed overall higher susceptibility to AFB(1)-related HCC in Gnmt-/- mice, further evidence that GNMT overexpression is an important contributing factor to liver cancer resistance.
Liu
Shih-Ping
SP
AIDS Prevention and Research Center, National Yang-Ming University, Taipei, Taiwan, Republic of China.
Li
Ying-Shiuan
YS
Lee
Cheng-Ming
CM
Yen
Chia-Hung
CH
Liao
Yi-Jen
YJ
Huang
Shiu-Feng
SF
Chien
Chau-Heng
CH
Chen
Yi-Ming Arthur
YM
D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D016604:Aflatoxin B1 / Q000633:toxicity*; D000818:Animals; D001344:Autopsy; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics*; D003433:Crosses, Genetic; D019388:Cytochrome P-450 CYP1A2 / Q000172:deficiency / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D017931:DNA Primers; D005260:Female; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000172:deficiency / Q000235:genetics; D050938:Glycine N-Methyltransferase / Q000172:deficiency*; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction / Q000379:methods; D014158:Transcription, Genetic
D018528:ATP-Binding Cassette Transporters; C508626:Abca8b protein, mouse; D017931:DNA Primers; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1; C414739:Cyp2d22 protein, mouse; D019388:Cytochrome P-450 CYP1A2; D000072467:Cytochrome P450 Family 2; D050938:Glycine N-Methyltransferase; C494511:Gnmt protein, mouse; C529117:GSTA4-4 protein, mouse; D005982:Glutathione Transferase