Comparative studies on the oxidation and reduction of drug substrates in human placental versus rat hepatic microsomes

Abstract

Human placental microsomes prepared by conventional methods were compared with analogous preparations from adult, male rat livers with respect to biochemical components and systems which could affect rates of mixed-function oxidation and reduction of drugs and steroids in vitro. Each of the electron transport components required for the mixed-function oxidation of drugs in hepatic systems was present in lower concentrations in placental than hepatic microsomes. In contrast to hepatic microsomes, placental microsomes which exhibited unusually high aryl hydrocarbon hydroxylase activities did not contain increased concentrations of the electron transport components. Evidence was provided to indicate that rapid degradation of initial electron donors (reduced pyridine nucleotides) was not responsible for the observance of low or negligible drug metabolic activities observed in incubations with placental micro-somes. Cytochromes P-450 and b 5 and their corresponding reductases were shown to be present in human placental preparations. NADPH and NADH-dependent cytochrome c reductase activities in placental microsomes were somewhat lower but comparable to those determined in hepatic preparations. However, cytochromes b 5 and P-450 and contaminating hemoglobin and methemoglobin accounted for less than 56 per cent of the total heme present in placental microsomes. Rapid degradation of placental cytochrome P-450 was observed at 37° in the presence of sodium hydrosulfite, but conversion to cytochrome P-420 was minimal after incubation for 1 hr in the presence of NADPH at the same temperature. It was con- sidered probable that the low rates of drug biotransformation observed would be explicable in terms of high substrate specificities of the placental enzymic components.