The enzymatic hydroxylation of 3,4-benzpyrene was not detected in human placentas obtained after childbirth from nonsmokers, whereas this enzyme activity was present in placentas obtained from individuals who smoked cigarettes. The degree of induction of benzpyrene hydroxylase caused by cigarette smoking varied in different individuals. Treatment of pregnant rats with benzpyrene increased the activity of this hydroxylase in the placenta.

Cigarette smoking markedly increases the activity of enzymes in human placenta which hydroxylate 3,4‐benzpyrene and N‐demethylate 3‐methyl‐4‐monomethylaminoazobenzene. No detectable benzpyrene hydroxylase or aminoazo dye N‐demethylase activity was observed in 17 human placentas obtained after childbirth from nonsmokers, but these enzymes were found in the placentas obtained from 17 smokers. Considerable variability in benzpyrene hydroxylase activity was observed in placentas that were obtained from women who smoke the same number of cigarettes. Several polycyclic aromatic hydrocarbons which are present in cigarette smoke were tested for ability to induce benzpyrene hydroxylase in rat placenta. Treatment of pregnant rats with 3,4‐benzpyrene, 1,2‐benzanthracene, 1,2,5,6‐dibenzanthracene, chrysene, 3,4‐benzofluorene, anthracene, pyrene, fluoranthene, perylene, or phenanthrene increased benzpyrene hydroxylase activity in the placenta.

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Experiments were carried out in dogs to investigate potentially dangerous interactions of drugs with bishydroxycoumarin that can occur in man. Dogs were treated orally with 1 mg. per kilogram of body weight of bishydroxycoumarin every other day for 39 to 44 days, and constant elevated prothrombin times and plasma levels of drug were obtained. When the dogs were given 10 mg. per kilogram of phenobarbital daily, the prothrombin time fell to normal and anticoagulant was no longer detectable in the plasma. If the dose of bishydroxycoumarin was then increased sevenfold, prothrombin times and plasma levels of drug were only slightly elevated. Phenobarbital administration was stopped, but bishydroxycoumarin was continued. Ten to 15 days after discontinuing phenobarbital, plasma levels of bishydroxycoumarin increased markedly, and all dogs developed severe hemorrhages. Administration of barbital also decreased the plasma level of bishydroxycoumarin and antagonized the activity of the anticoagulant, but barbital was less potent than phenobarbital. These effects can be explained by a stimulatory effect of the barbiturates on the metabolism of bishydroxycoumarin. When phenylbutazone and tolbutamide were given under the same conditions as the barbiturates, anticoagulant activity was first potentiated and then antagonized. This can be explained by initial displacement of bishydroxycoumarin from binding sites on plasma protein followed by a stimulatory effect of phenylbutazone and tolbutamide on the metabolism of bishydroxycoumarin.

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