Factors affecting hepatic drug metabolism in the pregnant rat.

Changes in hepatic drug metabolism during pregnancy have been characterised and the role of steroids and other hormonal factors investigated. Studies with human placental lactogen and rat placental homogenate suggest that during gestation elevated levels of circulating placental lactogen cause a significant decrease in maternal hepatic mixed-function oxidase activity when expressed per gram liver. Drug enzyme activity, determined with the substrates aniline (p-hydroxylation), ethylmorphine (N-demethylation) and p-nitrobenzoic acid (reduction), decreased progressively during gestation to 53-73% of non-pregnant control levels by day 20 of gestation. Enzyme activity remained low 1 day post-partum but had returned to control non-pregnant levels by 5 days post-partum. The total capacity of the liver to metabolise drugs remained unchanged or increased because liver weight was elevated by up to 40% during pregnancy. Alterations in hepatic drug metabolism are possibly mediated via changes in microsomal phospholipids and/or the cytochrome P450 spin state equilibrium. since pregnancy was associated with a significant decrease in (i) microsomal total phospholipids, (ii) the phosphatidylcholine to phosphatidylethanolamine ratio and (iii) the high-spin form of ferricytochrome P450. Changes in drug metabolism were not related to alterations in the concentration, substrate induced binding affinity (Ks) or maximal spectral change (AAMax) of cytochrome P450 or to the activity of NADPH-cytochrome c reductase. The rise in circulating steroids, particularly progesterone, during gestation does not appear to be an important modulator of mixed-function oxidase activity. The effect of phenobarbitone and 3-methylcholanthrene and of a choline supplemented diet on mixed-function oxidase activity during gestation has been investigated. The significance of changes in the haemoprotein spin state and microsomal phospholipids to hepatic drug metabolism has been discussed. Possible mechanisms of action of placental lactogen have been discussed with respect to the related polypeptide, growth hormone