Expression of xenobiotic-metabolizing CYPs in human pulmonary tissue

Tissue Distribution of mRNA Expression of Human Cytochrome P450 Isoforms Assessedby High-Sensitivity Real-Time Reverse Transcription PCR

“…Consistent with the ndings of another study, 10) CYP3A4 mRNA levels in the fetal liver were about 0.1 times lower than in the adult liver. The results for the CYP3A subfamily in the fetal liver and in adult organs such as the liver, small intestine, kidney, and lung are also consistent with the data reported by Raunio et al, 11) Zhang et al, 12) Lacroix et al, 10) and De Wildt et al 13) CYP2E1 showed the highest level of mRNA expression in the adult liver, and consistent with the ndings of other studies, 14,15) CYP2E1 mRNA levels were about 20 times higher than those of CYP3A4 in the adult liver. CYP2A6 showed the second highest level of mRNA expression in the adult liver.…”

“…The results for CYP1A1 and CYP1A2 mRNA in the small intestine, lung, and placenta were similar to those reported in the literature. 11,12,19) The results for CYP2B6, CYP2F1, and CYP4B1 mRNA in the lung were also similar to those reported in the literature. 11) CYP1A2, CYP2F1, and CYP4B1 were absent in the fetal liver, which is in agreement with the literature.…”

Naphthalene metabolism in relation to target tissue anatomy, physiology, cytotoxicity and tumorigenic mechanism of action

“…The CYP2F1 mRNA has been identified in human respiratory tissues by a number of different laboratories (see Raunio et al, 1999;Ding and Kaminsky, 2003). The CYP2F1 enzyme was expressed in lymphoblastoid cells and shown to metabolize naphthalene to its epoxide, albeit at very low rates (Lanza et al, 1999).…”

Hypothesis-based weight of evidence: A tool for evaluating and communicating uncertainties and inconsistencies in the large body of evidence in proposing a carcinogenic mode of action—naphthalene as an example

“…Epidemiology data are lacking To our knowledge, there are no cohort or case-control studies of naphthalene and cancer risk� There are only a few reports of individual cancer cases with prior naphthalene exposure (Griego et al�, 2008)� These include four smokers with laryngeal cancer among naphthalene purification workers in East Germany and 23 colon cancer cases, half of whom reported taking a treatment containing naphthalene (Griego et al�, 2008)� In no case can the cancer be definitively attributed to naphthalene� Also, none of these cancers occurred in the lung or nose� Exposure to polycyclic aromatic hydrocarbons (PAHs) in general has been associated with a modest increase in lung cancer risk (Bosetti et al�, 2007), but it is unclear if any of this risk is attributable to naphthalene� In contrast, to our knowledge, no studies have examined risks of nasal cancer from PAHs� It is conceivable that this is because nasal cancer is extremely rare, which makes it difficult to study epidemiologically, but nasal cancer has been studied and found to be associated with other environmental and occupational exposures in epidemiological studies (e�g�, insoluble nickel, see Goodman et al�, 2009)� Were PAHs in general, and naphthalene in particular, associated with nasal cancer risk, it certainly could have been studied� Even though the chances of a statistically significant association is low (owing to nasal cancer's low background rate), any occurrence of this rare cancer would have been notable� Yet, it has never been noted� Although this lack of evidence does not definitively show that naphthalene is not associated with nasal cancers in humans, it is certainly suggestive� Current in vitro data for naphthalene activity in humans Buckpitt and Bahnson (1986) showed that naphthalene is metabolized to its epoxide (as measured by presence of the dihydrodiol) in microsomal fractions of human lung tissue at about 3% the rate observed in rodents� Recombinant human lung CYP2F1 has been shown to metabolize naphthalene to its epoxide metabolite in human lymphoblastoid cells at very low rates Lanza et al�, 1999), and CYP2F1 mRNA has been identified in human respiratory tissue, but results in much lower expression than CYP2F4 in rats Raunio et al�, 1999;Ding and Kaminsky, 2003)� Currently, no studies have examined the involvement of CYP2F1 in the activation of naphthalene to its epoxide in actual human lung tissue, i�e�, in the presence of other CYPs and metabolic and detoxifying enzymes (GSH S-transferase, EH, and DD) in the human lung� It is important to point out that the naphthalene concentrations used in the bioassays exceeded the maximum tolerable dose (MTD) (North et al�, 2008), where nearly 100% chronic inflammation occurred in both rats and mice and in both sexes at all doses, indicating that cytotoxicity occurred at all doses� Although this does not in itself constitute proof, especially given the high exposure concentrations, these data suggest that cytotoxicity played a significant role in the observed naphthalene-induced tumor formation in both species� Therefore, since the concentrations used in these bioassays were about 3000-fold greater than naphthalene levels measured in ambient air (Griego et al�, 2008), low-dose extrapolation of these data to concentrations human...…”