Mixed function oxidation and intermediary metabolism: metabolic interdependencies in the liver.
Both hepatic lipogenesis from glucose and gluconeogenesis from lactate are inhibited by substrates for mixed function oxidation such as aminopyrine. These effects are inducible with phenobarbital pretreatment and absent with a demethylated product of aminopyrine metabolism, aminophenylpyrazolone. The data indicate that an interaction between biosynthesis and drug metabolism occurs in the intact liver cell. In the case of lipogenesis, direct competition for cytosolic NADPH occurs, whereas in the case of gluconeogenesisi, enhanced drug metabolism diverts key intermediates, e.g., malate from glucose synthesis toward NADPH generation. Furthermore, rates of mixed function oxidation were modified following perturbations of intermediary metabolism, e.g., fasting, addition of substrates for glucose synthesis, inhibition of energy metabolism, etc. The data support the hypothesis that in the presence of sufficiently high concentrations of substrate and oxygen, the rate-limiting step for mixed function oxidation in the intact cell is supply of NADPH.
D000632:Aminopyrine / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001711:Biotransformation; D004098:Dihydroxyacetone / Q000494:pharmacology; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D008055:Lipids / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism*; D009249:NADP / Q000378:metabolism*; D009575:Nitroanisole O-Demethylase / Q000378:metabolism; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D014316:Tritium; D014867:Water / Q000378:metabolism
D007773:Lactates; D008055:Lipids; D000632:Aminopyrine; D014867:Water; D014316:Tritium; D009249:NADP; D009575:Nitroanisole O-Demethylase; D005947:Glucose; D004098:Dihydroxyacetone; D010634:Phenobarbital