Polycyclic aromatic hydrocarbon (PAH) metabolizing enzyme activities in human lung, and their inducibility by exposure to naphthalene, phenanthrene, pyrene, chrysene, and benzo(a)pyrene as shown in the rat lung and liver

Abstract

In order to survey changes and activities in the polycyclic aromatic hydrocarbon (PAH)-metabolizing enzymes implicated in lung cancer susceptibility studies, we investigated enzyme induction by 2-5-ring-sized 'biomarker' PAHs in rat liver and lung, and the activities in five human lung specimens. Naphthalene, phenanthrene, pyrene, chrysene, and benzo[a]pyrene (BaP) were administered to rats for 3 days (25-128 mg/kg/day) and the responses compared with those of model inducers. PAH treatment increased the CYP1A-catalyzed activity of pyrene 1-hydroxylation and 7-ethoxyresorufin O-deethylation in rat liver by up to 28- and 279-fold, and in rat lung by up to 22- and 51-fold, respectively. 1-Naphthol (hUGT1A6), 1-hydroxypyrene (hUGT1A6/1A9), and entacapone (hUGT1A9) are markers of PAH-glucuronidating human uridine diphosphate-glucuronosyltransferases (UGT). These activities increased up to 6.4-fold in rat liver and up to 1.9-fold in rat lung. NADPH:quinone oxidoreductase 1 (NQO1) and glutathione S-transferase activities increased up to 5.3- and 1.6-fold (liver), and up to 4.4- and 1.4-fold (lung), respectively. CYP1A showed the best liver-to-lung relationship (R (2 )=( )0.90). The inducing efficiency by PAHs differed extensively: control <or= naphthalene < phenanthrene, pyrene << chrysene < BaP. In human lung (non-smokers), the marker activities of CYP1A1, UGT1A6/1A9, and NQO1 were lower than those in rat lung. Epoxide hydrolase activity was 1,000-fold higher than the pulmonary CYP1A1 activities. Human UGT and NQO1 displayed large variations (>60-fold), many times greater than the experimental (inducible/constitutive) variation in the rat. Kinetics of 1-hydroxypyrene glucuronidation showed two low-K (m) forms both in rat and human lung. Since the 2-4-ring PAHs (major constituents) were poor enzyme inducers, it appears that the PAH-metabolizing pathways are mainly induced by BaP-type minor constituents. Gene-environmental interactions which magnify polymorphic variability in pulmonary bioactivation/detoxification capacity probably play a key role in individual susceptibility to (or protection against) chemically induced lung cancer. Hence, human exposure to PAH mixtures with high content of BaP-type hydrocarbons confers a potentially higher health risk than PAH mixtures with low content of procarcinogens.

UGT2B Gene Expression Analysis in Multiple Tobacco Carcinogen-Targeted Tissues

“…The high interindividual differences in expression may be due to multiple genetic, epigenetic, and epidemiologic factors. Tobacco smoke is itself known to contain a number of agents that can induce UGT activity, and thus an individual's smoking habits are likely to influence UGT gene expression levels and enzymatic activity (Villard et al, 1998;Elovaara et al, 2007). However, as only basic demographic information was available for the subjects from whom these specimens were obtained and the smoking habits of the individuals were unknown, deductions regarding the potential influence of tobacco smoke induction of UGT genes could not be performed.…”

Molecular Markers Associated with the Biological Response to Aromatic Hydrocarbons from Urban Air in Humans

“…Gene-environmental interactions that magnify the polymorphic variability in the pulmonary bioactivation/detoxification capacity probably play a key role in individual susceptibility to or protection against, chemically-induced lung cancer. Hence, human exposure to PAH mixtures with a high content of BaP-type hydrocarbons confers a potentially higher health risk than PAH mixtures with a low content of pro-carcinogens (Elovaara et al, 2006).…”

Characterization of Endocrine Disruptors and Particulate Matter Emissions from Laser Cutting of Plastic Film in the TFT-LCD Industry

“…Previous studies have confirmed that most PAHs are potential environmental endocrine disruptors and they are carcinogenic and/or mutagenic (Grimmer, 1983;Elovaara et al, 2007;Smith et al, 2007). Animal studies found that some PAHs affected the function of estrogen and were related to infertility (Kummer et al, 2008;Smith et al, 2007).…”