A total hepatic induction index of metabolism for lipophilic xenobiotics.
A model for monitoring the hepatic ability to metabolize lipophilic xenobiotics is proposed. By identifying the behaviour of the mixed-function oxidase system as the rate determining feature of the response, an index can be devised from three independent factors: (i) the rate of the catalyzed reaction at each enzyme site, (ii) the concentration of such enzyme sites per hepatocyte and (iii) the total number of active hepatocytes available. Use of the model was tested by administering an acute oral dose of 1,2-benzanthracene to Sprague-Dawley rats. The above factors were measured in practical terms, these being (i) enzyme activity per time per mg protein, (ii) the concentration of enzyme per unit microsomal protein as well as the concentration of microsomal protein per unit liver weight and (iii) ratio of liver weight to body weight. After statistical analysis, it was found that each factor obeyed a different response curve characterized by a different ratio of growth to decay exponents. The product of these four measurable and physiologically discrete phenomena at any dose is the Total Hepatic Induction index. Together, the parameters that make up our model provide a means for inter- and intra-species comparisons as a response to various chemicals.
D000818:Animals; D001551:Benz(a)Anthracenes / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism; D004790:Enzyme Induction; D008658:Inactivation, Metabolic; D008055:Lipids; D008099:Liver / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000378:metabolism*; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D001551:Benz(a)Anthracenes; D008055:Lipids; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System; C030935:benz(a)anthracene; D006899:Mixed Function Oxygenases