Bioactivation of diesel exhaust particle extracts and their major nitratedpolycyclic aromatic hydrocarbon components, 1-nitropyrene and dinitropyrenes, by human cytochromes P450 1A1, 1A2, and 1B1

The genotoxicities of four samples of diesel exhaust particle (DEP) extract s (DEPE) and nine nitroarenes found in DEPE were investigated after activat ion catalyzed by human cytochrome P450 (P450) family 1 enzymes co-expressed with NADPH-cytochrome P450 reductase (NPR) in Escherichia coli membranes. The DEPE samples induced umu gene expression in Salmonella typhimurium TA15 35/pSK1002 without any P450 system and were further activated by human P450 1B1/NPR membranes. Moderate activation of the DEPE sample by P450 1A2/NPR membranes was also observed, but not by either P450 1A1/NPR or NPR membrane s. 1-Nitropyrene (1-NP) was strongly activated by human P450 1B1/NPR membra nes. 1,8-Dinitropyrene (1,8-DNP) was most highly activated by P450 1A1 and 1B1 systems for the three DNPs tested. In contrast, 1,3-DNP was inactivated by P450 1A1/NPR, 1A2/NPR, and 1B1/NPR systems and slightly activated by NP R membranes. 2-Nitrofluoranthene (2-NF) and 3-nitrofluoranthene (3-NF) show ed activities similar to I-NP after bioactivation by P450 1B1/NPR membranes . However, the genotoxicities of 6-nitrochrysene, 7-nitrobenz[a]anthracene, and 6-nitrobenzo[a]pyrene were all weak in the present assay system. Appar ent genotoxic activities of DEPE were very low compared with standard nitro arenes in the presence of P450s, possibly because unknown component(s) of D EPE had inhibitory effects on the bioactivation of I-NP acid I,8-DNP cataly zed by human P450 1B1. These results suggest that environmental chemicals e xisting in airborne DEP. in addition to 1-NP. 1,6-DNP. 1,8-DNP. 2-NF, and 3 -NF, can be activated by human P450 1B1. Biological actions of air pollutan ts such as nitroarenes to human extrahepatic tissues may be of concern in t issues in which P450 1B1 is expressed. (C) 2000 Elsevier Science B.V. All r ights reserved.