Inhibition of rat methylbenzylnitrosamine metabolism by dietary zinc and zinc in vitro.
Methylbenzylnitrosamine is an esophageal-specific carcinogen in the rat, and the incidence of methylbenzylnitrosamine-induced esophageal carcinoma is increased by dietary zinc deficiency. Methylbenzylnitrosamine requires activation by cytochrome P-450 to be mutagenic; the present study examined the role of dietary zinc deficiency and the in vitro addition of zinc on the cytochrome P-450-dependent microsomal metabolism of methylbenzylnitrosamine. Dietary zinc deficiency significantly increased the cytochrome P-450-dependent esophageal and hepatic microsomal metabolism of methylbenzylnitrosamine. These changes occurred without alteration in the specific content of total microsomal cytochrome P-450 of the esophagus or liver. The addition of zinc in vitro, at concentrations found in normal tissues, irreversibly inhibited the esophageal and hepatic cytochrome P-450-dependent microsomal metabolism of methylbenzylnitrosamine. These results suggest that physiological levels of zinc may be an endogenous inhibitor of methylbenzylnitrosamine metabolism. Dietary zinc deficiency appears to reduce this inhibition of cytochrome P-450 activity, resulting in an increase in carcinogen activation.
Barch
D H
DH
Department of Medicine, Northwestern University Medical School, Chicago, Illinois.
Fox
C C
CC
Rosche
W A
WA
Rundhaugen
L M
LM
Wrighton
S A
SA
D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000378:metabolism*; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives* / Q000378:metabolism; D004947:Esophagus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains; D015032:Zinc / Q000008:administration & dosage* / Q000172:deficiency*
D002273:Carcinogens; D003577:Cytochrome P-450 Enzyme System; C014707:nitrosobenzylmethylamine; D015032:Zinc; D004128:Dimethylnitrosamine