DNA hydroxyethylation by hydroxyethylnitrosoureas in relation to their organ specific carcinogenicity in rats.
N-Hydroxyethylnitroso-N'-ethylurea (HEENU) and N-hydroxyethylnitroso-N'-chloroethylurea (HCNU) are two of the few nitrosoureas which induce hepatocellular tumours in rats without further treatment. In the present study we have investigated whether this is due to selectively elevated levels of DNA hydroxyethylation in the target tissue. Formation of the promutagenic base O6-hydroxyethyldeoxyguanosine (O6-HEdG) in various rat tissues was determined by immuno-slot-blot assay. After a single dose by gavage (0.36 mmol/kg body wt) of HEENU, initial levels of O6-HEdG in liver and brain were close to the detection limit of 1.5 mumol/mol deoxyguanosine. In liver, steady state concentrations of 3.5 mumol/mol were reached after 6 h and maintained for at least 18 h. In brain, O6-HEdG levels were 1.7 mumol/mol after 6 h and 3.0 mumol/mol after 24 h. In a second experiment, the formation of O6-HEdG was assessed in target and non-target tissues 6 h after a single dose by gavage (0.36 mmol/kg) of HEENU, HCNU or hydroxyethylnitrosourea (HENU), which is not hepatocarcinogenic. The extent of DNA hydroxyethylation was greatest with HENU in all tissues examined. Concentrations of O6-HEdG were highest in liver (37.2 mumol/mol), followed by kidney (23.3 mumol/mol), lung (18.9 mumol/mol), brain (6.8 mumol/mol) and testes (3.8 mumol/mol). With HEENU and HCNU, levels of 1.4-3.3 mumol O6-HEdG/mol dG were observed in all tissues. In vitro, the alkylation reactions for all three compounds were nearly complete within 6 h. On a molar basis, yields of O6-HEdG in vitro were similar for HENU and HCNU and 3.7 times lower for HEENU. This suggests that the in vivo reactions of the dialkylnitrosoureas are by pathways other than or in addition to those occurring in vitro. We conclude that the hepatocarcinogenicity of HCNU and HEENU cannot be explained on the basis of their reaction with cellular DNA.
Ludeke
B
B
Department of Pathology, University of Zurich, Switzerland.
Schubert
M
M
Yamada
Y
Y
Lijinsky
W
W
Kleihues
P
P
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics*; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D005038:Ethylnitrosourea / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009928:Organ Specificity / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D013737:Testis / Q000187:drug effects / Q000378:metabolism
D002273:Carcinogens; C022146:1-(2-hydroxyethyl)-1-nitrosourea; D004247:DNA; D005038:Ethylnitrosourea