Trans-4-hydroxy-2-nonenal, an aldehydic lipid peroxidation product, lacks genotoxicity in lacI transgenic mice.
In order to cast light on the significance of lipid peroxidation products for carcinogenesis, the lacI mutant frequency (MF), micronucleus induction and cell proliferation were analyzed in lacI transgenic mice treated with trans-4-hydroxy-2-nonenal (HNE), a typical example. Male mice were ip injected with HNE at doses of 0, 5 or 50 mg/kg bw and 48 h thereafter, peripheral blood was collected for analyzing micronucleus induction. After 14 days, the mice were sacrificed to allow tissue sampling for examination of lacI MF and cell proliferative activity. Sixty percent of the mice given 50 mg/kg HNE died within 5 days after the treatment, but no other mortalities were observed. Histopathologically, marked pulmonary hemorrhage was found in the 50 mg/kg HNE group mice that survived until day 14. Immunohistochemically, HNE-modified proteins were detected in their alveolar macrophages. The HNE treatment did not increase lacI MF in the liver, kidney and lung and no significant increase in micronucleus induction or cell proliferation in major organs was found in either treatment. Moreover, no tumors developed in the 5 mg/kg HNE-treated mice which survived until week 78. Our results thus indicate that HNE lacks in vivo genotoxicity in lacI transgenic mice even when lethal doses are applied.
Nishikawa
A
A
Division of Pathology, National Institute of Health Sciences, Tokyo, Japan.
Furukawa
F
F
Kasahara
K
K
Ikezaki
S
S
Itoh
T
T
Suzuki
T
T
Uchida
K
K
Kurihara
M
M
Hayashi
M
M
Miyata
N
N
Hirose
M
M
D000447:Aldehydes / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics*; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000235:genetics; D029968:Escherichia coli Proteins; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D056968:Lac Repressors; D007928:Lethal Dose 50; D015227:Lipid Peroxidation; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015162:Micronucleus Tests; D016296:Mutagenesis; D009153:Mutagens / Q000633:toxicity*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D012097:Repressor Proteins / Q000235:genetics*; D012156:Reticulocytes / Q000187:drug effects / Q000378:metabolism; D019076:Transgenes / Q000235:genetics
D000447:Aldehydes; D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D056968:Lac Repressors; D009153:Mutagens; D018809:Proliferating Cell Nuclear Antigen; D012097:Repressor Proteins; D004247:DNA; C027576:4-hydroxy-2-nonenal