STYRENE METABOLISM BY CDNA-EXPRESSED HUMAN HEPATIC AND PULMONARY CYTOCHROMES P450

The rate of formation of styrene glycol from styrene was compared in h uman, rat, and mouse liver microsomes. At a low styrene concentration (0.085 mM), the rates decreased in the order, mouse (2.43 +/- 0.29 nmo l(mg of protein.min)) > rat (1.07 +/- 0.20) > human (0.73 +/- 0.45); a t a high concentration (1.85 mM), the order was rat (4.21 +/- 0.72) > mouse (2.72 +/- 0.11) > human (1.91 +/- 0.84). Kinetic analysis indica ted the presence of at least two forms of styrene metabolizing cytochr ome P450s with different K-m values in human liver microsomes. Styrene was also metabolized in human lung microsomes: the rate of styrene gl ycol formation was higher in the lung microsomes from smokers than in those from current nonsmokers. The P450 forms responsible for transfor ming styrene to styrene glycol were determined by analyzing cDNA-expre ssed individual P450 forms produced in cultured hepatoma G2 cells by r ecombinant vaccinia viruses. Of the 12 human P450 forms studied, CYP2B 6 and CYP2E1 existing in human liver and/or lungs and CYPBF1 in human lungs were the most active in the forming of styrene glycol, followed by CYP1A2 and CYP2C8. Human CYP3A3, CYP3A4, CYP3A5, and CYP4B1 also ca talyzed the metabolism but were much less active. CYP2A6, CYP2C9, and CYP2D6 had only a little detectable activity. CYP1A2, CYP2B6, CYP2C8, CYP2E1, and CYP3A4/3A3 were expressed in human liver microsomes, and C YP2C8 was expressed in human lung microsomes, although the expression of CYP2F1 and CYP4B1 could not be investigated. These data indicate th at several human hepatic