Abstract
Marked species differences in xenobiotics metabolism in the liver seriously limit extrapolations from animals to man. Because access to human liver is limited and periodic, we have set up a human “liver bank” available for metabolic studies. The liver tissue is obtained shortly after circulatory arrest from cadaveric (cerebral infarction) kidney transplant donors. Postmortem changes are minimal. Subcellular liver fractions are prepared immediately and part of this is used directly for assay. Intact pieces and subcellular fractions are stored in different media at −80°. Each liver is characterized by light and electron microscopy. Several enzymes, including cytochromes P-450 and b5, NADPH-cytochrome c reductase, demethylation of aminopyrine and amitriptyline, epoxidation of carbamazepine, oxidation of acetaminophen, and benzo[a]pyrene, were tested with freshly prepared fractions so that each liver got a “drug metabolic profile.” This “test battery” was repeated after storing to evaluate the effect of storage. Our preparation technique gave a well-preserved microsomal fraction with minimal contamination. In freshly prepared microsomes the following activities (levels) were observed: cytochrome P-450, 0.13 to 0.73 nmole/mg protein; NADPH-cytochrome c reductase, 70 to 426 nmole/mg protein; demethylation of aminopyrine, 0.9 to 4.1, and of amitriptyline, 0.11 to 0.92 nmole/mg protein; carbamazepine-10,11 epoxidation, 0.03 to 0.46 nmole/mg protein; oxidation of acetaminophen, 0.48 to 2.11, and of benzo[a]pyrene, 0.04 to 0.11 nmole/mg protein · min. These values are generally higher than in the literature. Our storage conditions were efficient: most of the activities were well preserved during storage for at least 6 mo. When pairs of enzyme activities (levels) were plotted against each other with fresh tissue there was good correlation between some but not all activities. Clinical Pharmacology and Therapeutics (1980) 27, 711–725; doi:10.1038/clpt.1980.102
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