DEVELOPMENTAL ASPECTS OF HEPATIC AND EXTRAHEPATIC DRUG-METABOLIZING ENZYME SYSTEMS: MICROSOMAL ENZYMES AND COMPONENTS IN RABBIT LIVER AND LUNG DURING THE FIRST MONTH OF LIFE

¹ Pharmacology and Toxicology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina

Rabbit lung microsomes metabolize a variety of chemicals and drugs at rates which are easily measured and often similar to rates using liver microsomes. Age-related changes in liver microsomal enzymes have been studied in detail, but similar studies in lung have not been made to our knowledge. We studied the development of cytochromes, cytochrome reductases and certain drug metabolisms in liver and lung microsomes at four ages: three to five days, two weeks, one month and four to six months (adult). Among the components studied, two general patterns of age-related changes appeared in the hepatic microsomes: 1) a gradual increase from three days to one month and 2) a discontinuous increase with a sharp jump in level between two weeks and one month of age. Reduced nicotinamide adenine dinucleotide phosphate-cytochrome c and P-450 reductase activities and cytochrome b₅ content followed the first pattern, whereas cytocimrome P-450 content, benzphetamine metabolism and benzpyrene hydroxylase activity followed the latter pattern. All the components studied in the lung showed a gradual linear increase in level or activity with age. In contrast to the liver, adult cytochrome levels and enzyme activities in lung microsomes were not reached at one month of age. Results suggest that age-related changes in microsomal enzymes occur in both liver and lung, but individual components behave differently in the two tissues. It was shown in both liver and lung that microsomal yield and total enzyme activity could be increased with improved cell breakup (by sonication of homogenates) without affecting enzyme specific activity as measured by benzphetamine metabolism. By comparing benzphetamine metabolism in the homogenates and 9000 x g supernatants in both lung and liver and at all four ages, it was shown that the age-related patterns of enzyme development as determined using only "microsomal" fractions were reasonably representative of the whole organ's development of these xenobiotic metabolizing systems.

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