p-Chloro-N-methylaniline demethylase activity in liver and extrahepatic tissues of the human fetus and in chick embryo liver

AB Rifkind and T Petschke

We achieved a 50-fold increase in sensitivity of a fluorescence assay for p-chloro-N-methylaniline (p-CNMA) demethylase enabling us to examine the kinetics of the reaction in chick embryo liver and human fetal tissues and its inducibility in chick embryo liver. In chick embryo liver, p-CNMA demethylase activity was maximally induced (to about 200% of control levels) by both phenobarbital and beta- naphthoflavone. p-CNMA demethylase is therefore nonselective in its response to inducers of the P-450 and P-448 classes, respectively. Line- weaver-Burk plots of the data suggest that single kinetic components predominated in the reaction for both control and induced livers (mean apparent KmS: control, 3.8 X 10(-5) M; phenobarbital treated, 3.8 X 10(- 5) M). Differences in the KmS and the pH-activity curves for the phenobarbital- and beta-naphthoflavone-induced enzymes suggested, however, that the induced enzymes were not identical. p-CNMA demethylase activity was measurable in liver and extrahepatic organs of the human fetus and was 1.5 times higher in human fetal liver than in chick embryo liver. At least two kinetic components participated in the reaction in the human liver. Reaction rates in human fetal adrenal, lung and brain were about 60, 2 and 1% of the liver rates, respectively. Detection of mixed function oxidase activity in human fetal brain, not usually considered a site of biotransformation, suggests that the fetal brain could be a site of cytotoxic activation of chemicals during human fetal development.

Volume 217, Issue 3, pp. 572-578, 06/01/1981
Copyright © 1981 by American Society for Pharmacology and Experimental Therapeutics