Hepatic lipid metabolism. Age-related changes in triglyceride metabolism.

Age-related changes in hepatic triglyceride formation have been described in developing rats. Triglyceride formation was measured in vitro in the presence of [14C]glycerol-3-phosphate, palmitate, ATP, CoA, and Mg2+ by using liver homogenates and microsomal fractions derived from various age groups of animals. Triglyceride formation was most active in one-day-old rats and then decrease with age. The increase in triglyceride formation following birth was prevented by the administration of puromycin or by denying suckling. In addition, changes in plasma and hepatic triglyceride concentrations, were also determined as functions of age. These studies suggest that the age of the animal significantly influences triglyceride metabolism.     

Hepatic metabolism of artemisinin drugs--I. Drug metabolism in rat liver microsomes.

1. In this communication, metabolism of the semisynthetic antimalarial drugs of the artemisinin class (beta-arteether, beta-artelinic acid and dihydroartemisinin) in rat liver microsomes, is reported. 2. Dihydroartemisinin was the major early metabolite of arteether (57%) and artelinic acid (80%); in addition, arteether was hydroxylated in the positions 9 alpha- and 2 alpha- of the molecule. 3. Dihydroartemisinin was further metabolized by extensive hydroxylation of its molecule; we were able to identify four hydroxylated derivatives of DQHS, but not the exact positions of the hydroxyl groups. 4. The rates of NADPH-supported metabolism of arteether, artelinic acid and dihydroartemisinin in rat liver microsomes were: 4.0, 2.5 and 1.3 nmol/min/mg of microsomal protein, respectively. 5. The apparent affinity constants of arteether and artelinic acid for the microsomal metabolizing system, calculated from the rates of product formation, were 0.54 mM and 0.33 mM (for arteether) and 0.11 mM (for artelinic acid), respectively. The appearance of two affinity constants indicated that arteether was metabolized by two different isoenzymes of cytochrome P-450 in rat liver microsomes.     

Pulmonary metabolism of epoxides.

Activities of epoxide hydrase (EH) and glutathione S-transferase (GST) have been measured in pulmonary tissue from several species. On the basis of total organ activity, pulmonary tissue has less capacity than liver tissue to metabolize epoxides. Pulmonary EH and GST appear to be refractory to induction by typical agents. Rat pulmonary GST will conjugate a variety of epoxides, but K-region epoxides are metabolized at lower rates than alkene oxides. In the isolated perfused rabbit lung, benzo (a) pyrene-4,5-oxide (BPO) is metabolized by EH and GST at similar initial rates, but EH activity is lost after a few minutes, apparently owing to inadequate local substrate levels. GST from rabbit lung cytosol has been separated by chromatographic methods into six peaks of enzymic activity (toward 1-chloro-2,4-denitrobenzene). Of these peaks, all six metabolized BPO and two metabolized styrene oxide. Although EH and GST are less active in lung than in liver, pulmonary metabolism of epoxides is important because this tissue must be able to protect itself from arene oxides generated by pulmonary oxidative metabolism of polycyclic aromatic hydrocarbons.