81907-82-6Relevant articles and documents
Formate Oxidase (FOx) from Aspergillus oryzae: One Catalyst Enables Diverse H2O2-Dependent Biocatalytic Oxidation Reactions
Tieves, Florian,Willot, Sébastien Jean-Paul,van Schie, Morten Martinus Cornelis Harald,Rauch, Marine Charlène Renée,Younes, Sabry Hamdy Hamed,Zhang, Wuyuan,Dong, JiaJia,Gomez de Santos, Patricia,Robbins, John Mick,Bommarius, Bettina,Alcalde, Miguel,Bommarius, Andreas Sebastian,Hollmann, Frank
supporting information, p. 7873 - 7877 (2019/05/10)
An increasing number of biocatalytic oxidation reactions rely on H2O2 as a clean oxidant. The poor robustness of most enzymes towards H2O2, however, necessitates more efficient systems for in situ H2O2 generation. In analogy to the well-known formate dehydrogenase to promote NADH-dependent reactions, we here propose employing formate oxidase (FOx) to promote H2O2-dependent enzymatic oxidation reactions. Even under non-optimised conditions, high turnover numbers for coupled FOx/peroxygenase catalysis were achieved.
Product inhibition and dose-dependent bioavailability of propranolol in the isolated perfused rat liver preparation
Ghabrial,Nand,Stead,Smallwood,Morgan
, p. 931 - 936 (2007/10/02)
We investigated in the isolated perfused rat liver (IPRL) whether product inhibition of metabolism contributes to the dose-dependent bioavailability of propranolol, a drug with a high, but saturable, hepatic first-pass effect. (±)-Propranolol was infused in the IPRL, using a recirculating design, for three 36-min periods (n = 9). Mean steady-state reservoir, i.e. hepatic inflow concentrations (C(in)), were 4.97, 10.4, and 20.4 μM, respectively. Mean reservoir concentrations of the metabolites 4'-hydroxypropranolol, 5'- hydroxypropranolol, N-desisopropylpropranolol, and naphthoxylactic acid (NLA), a major side-chain-oxidation metabolite, increased disproportionately with propranolol dose, but their production rate did not reach steady state. In separate experiments (n = 4), perfusate containing 7.1, 12.8, and 21.6 μM (±)-propranolol, corresponding to administration rates of 114, 205, and 346 nmol/min, respectively, was passed through the liver for 30 min each using a single-pass design. The bioavailability (hepatic outflow concentration/C(in)) of propranolol increased with C(in) from 0.012 to 0.150 to 0.288 in the recirculating IPRL. In the single-pass IPRL the increase (0.0077 in 0.0669 to 0.136) was significantly less (P 0.001). The greater bioavailability of propranolol in recirculating experiments was attributed to product inhibition since metabolites do not accumulate with the single-pass design. NLA did not appear to be the inhibiting metabolite because in further single-pass experiments with propranolol C(in) of 21.6 μM the presence of NLA (21.6 μM) in perfusate had no effect on propranolol bioavailability (n = 7) compared with control experiments (n = 5). These data suggest that, with the recirculating IPRL, dose-dependent bioavailability of propranolol is due to competitive inhibition of propranolol metabolism by propranolol metabolites, which is distinct from the noncompetitive product inhibition that has been reported to accompany chronic propranolol administration.