Suppression of in vivo clearance of N-nitrosodimethylamine in mice by cotreatment with ethanol.
Oral cotreatment of mice with ethanol results in increased tumors in extrahepatic organs caused by some nitrosamines. This action, attributed in part to inhibition of hepatic first-pass carcinogen metabolism by ethanol, has possible relevance to the enhancing effect of alcoholic beverage consumption on human cancer risk. In this study, the effects of ethanol on clearance of N-nitrosodimethylamine (NDMA) were quantified in Swiss female and strain A male mice. In Swiss mice, a 1.6 g/kg ig ethanol dose preceding 1 or 5 mg/kg iv NDMA resulted in 20- to 30-fold increases in area-under-the-blood-concentration-vs.-time curves, mean residence times, and clearance half-times, and similar decreases in clearance. For a 0.5 mg/kg ig NDMA dose, the pharmacokinetic parameters were altered 30-fold and 450-fold by simultaneous ethanol doses of 0.08 and 0.8 g/kg, respectively. With 5 mg NDMA/kg ig, 0.4, 0.8, and 1.6 g/kg ethanol resulted in 6-, 10-, and 20-fold changes in clearance parameters. Comparison of the data with results obtained previously with patas monkeys indicated comparable effects of ethanol on tissue exposure to NDMA in the two species, confirming potential human applicability. In experiments with strain A mice, NDMA concentrations were also monitored in lung and liver. NDMA amounts in lung paralleled those in blood, and were more than sufficient to account for the previously reported increases in DNA adducts and tumors in lungs of similarly treated strain A mice.
Anderson
L M
LM
Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick, MD 21702.
Koseniauskas
R
R
Burak
E S
ES
Logsdon
D L
DL
Carter
J P
JP
Driver
C L
CL
Gombar
C T
CT
Magee
P N
PN
Harrington
G W
GW
D000818:Animals; D004128:Dimethylnitrosamine / Q000097:blood / Q000493:pharmacokinetics*; D000431:Ethanol / Q000008:administration & dosage* / Q000097:blood; D005260:Female; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008805:Mice, Inbred A
D000431:Ethanol; D004128:Dimethylnitrosamine