Drug metabolism in man and its relationship to that in three rodent species: monooxygenase, epoxide hydrolase, and glutathione S-transferase activities in subcellular fractions of lung and liver.
Activities of drug metabolizing enzymes were determined in subcellular fractions of lung biopsies from 12 human subjects and in liver biopsies from 15 other human subjects. Monooxygenase (MO) activity with 7-ethoxycoumarin as a substrate and epoxide hydrolase (EH) activity with benzo[a]pyrene 4,5-oxide as a substrate were measured in the microsomal fraction, glutathione S-transferase (GST) activity toward 2,4-dinitrochlorobenzene in the cytosolic fraction. MO activity was further characterized by the use of inhibitors known to act preferentially on different MO forms. To facilitate extrapolations from test results obtained in animals to man enzyme activities were also determined in corresponding fractions from commonly used laboratory animals, Sprague-Dawley rat, NMRI mouse, and Syrian golden hamster. All investigated specific activities were lower in lung than in liver preparations by factors ranging from 2.4 to 7 in the mouse, 4 to 18 in rat and hamster, and 11 to 697 in man. The high ratio between liver and lung activity in man occurred with MO and is due to an extremely low activity in human lung. It is not clear whether this low activity is predominantly due to low amounts of enzyme or to inhibitors known to be present in human lung preparations. With this exception of human lung MO, species differences in the investigated enzyme activities were moderate. Among the three rodent species, rat was most similar to man, with none of the investigated activities differing by a factor more than 2. The mouse differed from these two species by considerably higher MO and GST activities in both organs, and by a relatively low EH activity in liver for the investigated substrates, while the hamster displayed comparatively high lung GST and EH and liver GST and MO activities. MO inhibition patterns by different in vitro inhibitors were similar in the same organs of different species, but differed in lung and liver. Standard concentrations of the diagnostic inhibitors led to preferential inhibition of lung MO by metyrapone and considerably less by tetrahydrofuran, while for liver MO the reverse was true. In both organs, the standard concentration of alpha-naphthoflavone had only very weak effects. In conclusion, man and commonly used laboratory rodents are not grossly different with respect to the investigated enzyme activities with the possible exception of lung MO. For the substrates investigated, the rat represented clearly the best model for man among the studied animal species.
D000328:Adult; D000368:Aged; D000818:Animals; D001580:Benzopyrenes / Q000378:metabolism; D003374:Coumarins / Q000378:metabolism; D006224:Cricetinae; D004137:Dinitrochlorobenzene / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000378:metabolism*; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000201:enzymology*; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology*; D008875:Middle Aged; D010105:Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013347:Subcellular Fractions / Q000201:enzymology
D001580:Benzopyrenes; D003374:Coumarins; D004137:Dinitrochlorobenzene; D004364:Pharmaceutical Preparations; C017299:7-ethoxycoumarin; C006707:benzo(a)pyrene 4,5-epoxide; D010105:Oxygenases; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases