The effect of repetitive oral administration of propranolol on hepatic microsomal drug metabolizing enzyme activities in the rat was investigated. Propranolol ring (4-, 5- and 7-)hydroxylase activities were markedly decreased, but, interestingly, N-desisopropylase activity was increased after propranolol administration. A marked decrease in enzyme activity after propranolol pretreatment was also observed with debrisoquine 4-hydroxylation. In addition, a similar decrease was observed with imipramine 2-hydroxylation which co-segregates with debrisoquine/sparteine type polymorphic drug oxidation, but not with imipramine N-demethylation. These results suggest the selective impairment of debrisoquine 4-hydroxylase by propranolol pretreatment.

Animals↗

PubMedDate not supplied

Purification and characterization of a cytochrome P-450 isozyme catalyzing bunitrolol 4-hydroxylation in liver microsomes of male rats.

A cytochrome P-450 isozyme, P-450 bunitrolol (BTL), catalyzing bunitrolol 4-hydroxylation was partially purified from liver microsomes of adult male Sprague-Dawley rats by hydrophobic affinity chromatographic (omega-aminooctyl-Sepharose 4B) and high-performance liquid chromatographic (anion-exchange diethylaminoethyl-5PW) techniques. The specific content of the final preparation was 5.02 nmol/mg protein, which was 7.8-fold that of microsomes. It showed two protein bands of 49 and 32 kDa in sodium dodecylsulfate-polyacrylamide gel electrophoresis. N-Terminal 20 amino acid sequence of the protein of a higher molecular mass (49 kDa) isolated by an electroblotting technique is 94% homologous with that of CYP2D2. In a reconstituted system including NADPH-cytochrome P-450 reductase and an NADPH-generating system, the final preparation had the highest activity toward BTL and debrisoquine 4-hydroxylation among 12 isozymes of cytochrome P-450 examined. Kinetic parameters, KM and Vmax values, of P-450 BTL calculated for BTL 4-hydroxylation were 10.7 microM and 19.68 nmol/min/nmol P-450, respectively, whereas those values (mean +/- SE) of rat liver microsomes were 0.84 +/- 0.05 microM and 2.05 +/- 0.11 nmol/min/nmol P-450. When preincubated with rat liver microsomes, the antibody against the final P-450 BTL preparation suppressed bunitrolol and debrisoquine 4-hydroxylase activities dose-dependently and almost completely. These results suggest that cytochrome P-450 BTL and its immunochemically related P-450 isozyme(s) play a major role in debrisoquine 4-hydroxylation as well as in BTL 4-hydroxylation in rat liver microsomes.

Amino Acid Sequence↗

PubMedDate not supplied

Hemodynamic and hemolytic features of the St. Jude Medical valve prostheses.

We performed valvular replacement in 86 cases (108 valves, 43 males, 43 females) from July 1978 to July 1981 with St. Jude Medical valves which utilize two discs made of pyrolytic carbon and employ a bileaflet central opening system. Ages ranged from 13 to 68 years (average 42.3). For all cases in this study, we performed anti-coagulant therapy. The incidence of thromboembolic complication was zero. With regard to postoperative clinical evaluation on valve function and chronic hemolysis, we compared the cases of St. Jude Medical valves with those of Starr-Edwards (S.E.) valves (aortic: Model 2320, mitral: Model 6400), Carpentier-Edwards (C.E.) valves and cases of open mitral commissurotomy. As for valve function such as left atrioventricular diastolic pressure gradient, mitral effective orifice area both at rest and on exercise, the St. Jude Medical valve yielded best results. Next was the C.E. and third was the S.E. The results of the St. Jude Medical valve group and those of the open mitral commissurotomy group were equivalent. In comparison with ball type cardiac valve prostheses and bioprostheses, the St. Jude Medical valve has excellent hemodynamic characteristic. Concerning hemolysis, the St. Jude Medical was below only the C.E., however the degree of hemolysis was so low that the St. Jude Medical valve holds great promise as central flow mechanical valve prostheses.

Adolescent↗