title: 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.
authors.affiliation: Finnish Institute of Occupational Health, 00250, Helsinki, Finland. Eivor.Elovaara@ttl.fi
authors.forename: Eivor
authors.initials: E
authors.lastname: Elovaara
authors.forename: Jouni
authors.initials: J
authors.lastname: Mikkola
authors.forename: Helene
authors.initials: H
authors.lastname: Stockmann-Juvala
authors.forename: Leena
authors.initials: L
authors.lastname: Luukkanen
authors.forename: Helena
authors.initials: H
authors.lastname: Keski-Hynnilä
authors.forename: Risto
authors.initials: R
authors.lastname: Kostiainen
authors.forename: Markku
authors.initials: M
authors.lastname: Pasanen
authors.forename: Olavi
authors.initials: O
authors.lastname: Pelkonen
authors.forename: Harri
authors.initials: H
authors.lastname: Vainio
mesh_terms: D000818:Animals; D001564:Benzo(a)pyrene / Q000494:pharmacology*; D002911:Chrysenes / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008168:Lung / Q000201:enzymology*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology*; D010616:Phenanthrenes / Q000494:pharmacology*; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism*; D011721:Pyrenes / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002911:Chrysenes; D020719:Glucuronides; D009281:Naphthalenes; D010616:Phenanthrenes; D011084:Polycyclic Aromatic Hydrocarbons; D011721:Pyrenes; C031180:chrysene; C031721:naphthalene; D001564:Benzo(a)pyrene; C031181:phenanthrene; C030984:pyrene; D019363:Cytochrome P-450 CYP1A1; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat