Interindividual variability of cytochrome P450 (CYP)-dependent alkoxyresorufin-dealkylase activities in human lung and relevance for the risk assessment of chemicals

Abstract

Background : The lung represents an important target for the toxic effects of chemicals. Target tissue toxicity can be explained by local metabolic activation. As demonstrated by mRNA and Western Blot analysis, xenobiotic metabolizing CYPs are expressed in human lung. Their variation within the human population isnot known, although this is important for the risk assessment of chemicals. From interindividual variability , pathway-specific assessment factors (AFs) can be derived. This is of special importance in the lung, where metabolism is capacity-limited due to low abundance of CYPs. We determined the variability of CYP450-related ethoxyresorufin- O -deethylase- (EROD-), methoxyresorufin- O -demethylase- (MROD) and pentoxyresorufin- O -depentylase- (PROD) activities in a large panel of human lung samples. The activities are related to CYP1A1/1B1 (EROD), CYP1A2 (MROD) and CYP2B enzymes (PROD). Methods : Human lung tissue was obtained after informed consent. Microsomes were prepared and total protein content was determined. Enzyme activitieswere determined using fluorometric methods for dealkylation of alkoxyresorufins modified for human lung tissue. Assessment factorswere derived by the ratio of the 95% percentile (P95)/median. Results : EROD-, MROD-, and PROD activities were determined in 110 samples. The following P95/median ratios were obtained: 2.7 (EROD), 2.9 (MROD) and 3.2 (PROD). For an improved risk assessment, enzymes involved in chemical metabolism should beidentified. Determination of enzyme variation allows replacing the default AF of 3.16 for the kinetic part of intraspecies variability by apathway-specific AF. Our results demonstrate that the pathwayspecific AF for the enzyme activities investigated in the lung is almost equal to the default AF of 3.16.