The application of physiologically based phatmacokinetic (PBPK) modeling allows the tissue specific concentration of xenobiotics to be estimated for application in human health risk assessment. The impact of metabolic variance on the pharmacokinetics of environmental toxicants can be estimated by accurately quantifying the expression of the pertinent enzyme(s) in human tissues. We have examined the expression of 1) microsomal protein (MP) in human liver tissue, and 2) CYP 1A, 2A, 2B, 2C, 2D, 2E and 3A forms in MP from ten adult human organ donors. Liver contained 31.9 +/- 9.3 (mean +/- SD) mg MP/gram intact tissue. MP contained 61 +/- 26 pmoles CYP2El/mg; and liver contained and 1921 +/- 775 pmoles CYP2El/gram tissue; MP contained 21.5 +/- 16.7 pmoles CYP1A/mg; and liver contained 669 +/- 585 pmoles CYP1A/gram tissue; MP contained 98 +/- 33 pmoles CYP3A/mg; and liver contained 2943 +/- 962 pmoles CYP3A/gram tissue. Liver content of MP appeared not to be correlated with either MP content of CYP2E1 or CYP1A, thus statistical methods may be employed to combine the smaller data set describing the MP content of liver with a larger data set (n = 141; Tox Sci 54(1): 181, #854) describing the expression of CYP enzymes in hepatic MP to extrapolate the hepatic content of CYP2E1 and other CYP forms. In contrast, liver content of MP and MP content of CYP3A appeared to be negatively correlated, indicating that a detailed investigation of their interrelationship must be undertaken prior to combining separate data sets describing the MP content of CYP3A and the liver content of MP. These data can be combined with data describing the specific activity of CYP forms towards substrates to develop metabolic rates, and their bounds, useful for inclusion in PBPK models developed to assess the impact of metabolic variance on risk.
The Toxicologist. Society of Toxicology 40th Annual Meeting, March 25-29, 2001, San Francisco, California