Monoclonal antibody phenotyping of interindividual differences in cytochrome P-450-dependent reactions of single and twin human placenta.
Cytochromes P-450 are a family of enzymes responsible for metabolism of drug and xenobiotics, such as carcinogen, and certain physiological compounds, such as steroids and prostaglandins. We prepared a monoclonal antibody (MAb 1-7-1) to a polycyclic hydrocarbon-induced rat cytochrome P-450 that antigenically defines and inhibits a type of cytochrome P-450 responsible for aryl hydrocarbon hydroxylase (AHH) and 7-ethoxycoumarin deethylase (ECD) activity in human placenta. We examined the placentas from single and twin births from mothers who smoked cigarettes and nonsmokers. The MAb 1-7-1 inhibited the smoking-induced AHH activity of essentially the entire population of placentas by 70 to 95%. Thus, up to 95% of the AHH in a population of human placentas is catalyzed by a type of cytochrome P-450 that contains an antigenic site recognized by MAb 1-7-1. A second type of cytochrome P-450, which is insensitive to MAb 1-7-1, is responsible for the ECD activity in the placentas of nonsmokers. In the placentas from smokers, both types of P-450 contribute to ECD activity. Their ratios can be determined by the amount of inhibition by MAb 1-7-1 which ranges from 0 to 70%. The placentas from both dizygotic and dichorionic monozygotic twins show extraordinarily high intrapair concordance for both the absolute amounts of AHH and ECD and their inhibition by MAb 1-7-1 compared with unrelated individuals, indicating that interindividual differences in these parameters of biological activity are not due to random variation or experimental error. Our results show that the amount of activity of antigenically unique types of cytochrome P-450 responsible for different drug and carcinogen reactions can be measured in different individuals by the amount of their inhibition by highly specific monoclonal antibodies. These findings may have general application to studies on the relationship cytochrome P-450 phenotype to population differences in drug and carcinogen biotransformation.
D015660:7-Alkoxycoumarin O-Dealkylase; D000911:Antibodies, Monoclonal; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008861:Microsomes / Q000378:metabolism; D010105:Oxygenases / Q000235:genetics; D010641:Phenotype; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D012907:Smoking; D014427:Twins; D014429:Twins, Dizygotic; D014430:Twins, Monozygotic
D000911:Antibodies, Monoclonal; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D001189:Aryl Hydrocarbon Hydroxylases