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Warfarin and diphenylhydantoin (DPH) were displaced from plasma proteins in rats by in vivo elevation of free fatty acids (FFA) produced by exercise or by i.p. injection of d,l-epin

A 3′-phosphoadenylylsulphate:steroid sulphotransferase is localised in the 150 000 × g supernatant of normal human liver. The enzyme was purified 22-fold by (NH4)2SO4 precipitation, by gel filtration of the precipitate through Sephadex G-200 and by chromatography on DEAE-cellulose. After incubation of the enzyme with dehydroepiandrosterone as substrate, the reaction product isolated was identified as dehydroepiandrosterone sulphate by paper chromatography, various micro-chemical reactions and crystallization with authentic carrier to constant specific activity. The sulphotransferase showed a pH optimum at 7.4 in Tris-HCl buffer. The Michaelis-Menten constants were found to be 6.7·10−6 M for dehydroepiandrosterone and 4.0·10−6 M for 3′-phosphoadenylylsulphate. The enzyme lost its activity within 6 days when stored at 4°; however, at −20°, the enzyme was stable for at least 4 months. The steroid sulphotransferase showed a temperature optimum at 50° and an activation energy of 22.2 kcal/mole, within the range of 37–50°. By gel filtration, using Sephadex G-200, the molecular weight of the sulphotransferase was found to be approximately 50 000. The activity of the purified enzyme preparation was not influenced by the addition of cystein or EDTA. In relatively high concentration, SH-blocking agents had an inhibitory effect. The addition of Co2+, Ni2+, Ca2+ and Mn2+ activated the enzyme, whereas Cu2+, Zn2+, Fe2+ and Hg2+ inhibited the sulphotransferase. The steroid sulphotransferase from human liver conjugates not only dehydro-epiandrosterone (100%), but also (although to a lower extent) 3α-hydroxy-5β-androstan-17-one (45%), oestriol (31%), oestradiol-17β (15%) and oestrone (8%). Testosterone and cholesterol were not conjugated by the enzyme.

An S-adenosylmethionine:catechol-O-methyltransferase (EC 2.1.1.6) is localised in the 150 000 × g supernatant of human placenta. The enzyme was purified 66-fold by (NH4)2SO4 precipitation and by repeated filtration of the (NH4)2SO4 precipitate through a Sephadex G-100 column. After incubation of epinephrine and S-[Me-14C]-adenosylmethionine, the main metabolite was identified as metanephrine (3-O-methyl-adrenalin). In the pH range of 6–8, the activity of the enzyme increased steadily. The Michaelis-Menten constants were found to be 43.5·10−5 M for epinephrine and 7.8·10−5 M for S-adenosylmethionine. The purified catechol O-methyltransferase was active for more than 3 months when stored at −20°. The enzyme shows a temperature optimum at 50° and an activation energy of 17.3 kcal/mole within the range of 24–42°. By gel filtration, using Sephadex G-100, the molecular weight of the placental catechol O-methyltransferase was found to be 52 000. The purified enzyme preparation was only active in the presence of cysteine (20–80 mM). In addition to epinephrine, other catechols were also methylated. When 2-hydroxyoestradiol-17β was used as substrate, 2-methoxyoestradiol-17β as well as 2-hydroxyoestradiol-17β 3-methyl ether were formed as metabolites. The methylation of epinephrine to metanephrine was inhibited competitively by 2-hydroxyoestradiol-17β.

The effect of renal failure on the excretion of oral doses of practolol has been studied. The plasma half-life increased up to 6.6 times normal and the cumulative urinary excretion of the drug was reduced. There was a linear correlation between the overall elimination rate constant of practolol and inulin and creatinine clearances. A linear correlation was also found between the renal clearances of practolol and inulin. The dose of practolol required for maintenance therapy should be reduced in patients with impaired renal function.

The half-life of antipyrine in plasma was studied In four hyperthyroid and four hypothyroid patients before and after thyroid status returned to normal. The half-life (± S.E.M.) was 7.9 ± 1.0 hours In hyperthyroid and 17.3 ± 1.1 hours in hypothyroid patients. After correction of the abnormal thyroid state the half-life values of both groups (12.3 ± 0.7 and 12.0 ± 0.5 hours) were within the normal range. These results suggest that abnormalities of thyroid function can markedly influence human metabolism of some drugs. (N Engl J Med 290:1040–1042, 1974)

Im Tierexperiment konnte gezeigt werden, das durch die Hyperthyreose und die Hypothyreose eine Reihe von Metabolisierungsschritten beeinflust sind, welche durch die mischfunktionellen Oxygenasen des endoplasmatischen Reticulum der Leber ausgefuhrt werden. So sind z. B. in vitro die N-Demethylierung von Morphin [1] und die aliphatische Hydroxylierung von Hexobarbital [2] sowohl bei hyperthyreoten als auch bei hypothyreoten Ratten herabgesetzt, wahrend die aromatische Hydroxylierung von Anilin [3] durch eine Uberfunktion der Schilddruse beschleunigt wird.

A S-adenosylmethionin: catechol-O-methyltransferase, which catalyses the methylation of catecholamines and of 2-hydroxyoestrogens, is localised in the 150000 × g supernatant of human placenta. The enzyme was purified 66fold by ammonium sulphate precipitation and by repeated filtration of the ammonium sulphate precipitate through a Sephadex G-100 column. In the pH range of 6–8, the activity of the enzyme increased steadily. The Michaelis-Menten constants were found to be 43.5 × 10−5 M for adrenaline and 7.8 × 10−5 M for S-adenosylmethionine. The enzyme shows a temperature optimum at 50° the activation energy of the reaction was 17.3 kcal/mole within the range of 24–42°. The methylation of adrenaline is inhibited by 2-hydroxyoestradiol-17β The inhibitor constant was found to be 17.4 × 10−6 M.