| Xenobiotic-metabolizing cytochrome P450 enzymes in human lung | ||
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Knowledge about the regulation of CYPs in human lung is rather limited. Virtually nothing is known about the tissue-specific expression of certain pulmonary CYP enzymes, such as CYP4B1 and CYP2F1, which are quite strictly lung-specific. Tobacco smoking does not induce CYP4B1 (Czerwinski et al. 1994).
By far the greatest amount of information has been gathered concerning the induction of CYP1A1 and CYP1A1-related enzyme activities AHH and EROD (Wheeler & Guenthner 1991). Both AHR and ARNT are expressed in human lung (Roberts et al. 1986, Hayashi et al. 1994). CYP1A1 protein is only detected in smokers (Anttila et al. 1991), and CYP1A1 expression correlates positively with the AHH and EROD activities in human lung tissue (McLemore et al. 1990, Wheeler et al. 1990, Anttila et al. 1991, Anttila et al. 1992, Bartsch et al. 1992). AHH activity decreases to the basal level within 2 months and CYP1A1 mRNA expression within 6 weeks after cessation of smoking (Petruzzelli et al. 1988, McLemore et al. 1990). CYP1A1 mRNA expression in the lung is more than 2-fold higher in female smokers compared with male smokers (Mollerup et al. 1999). It has been speculated that the complex interactions between the estrogen receptor and AHR pathways could explain this difference (Mollerup et al. 1999). CYP1B1, which is controlled by AHR/ARNT, is also induced by tobacco smoking in bronchial epithelium and alveolar macrophages (Willey et al. 1997, Piipari et al. 2000). AHH activity in alveolar macrophages is increased by smoking (Cantrell et al. 1973), and since CYP1A1 is neither expressed nor induced in these cells (Anttila et al. 1991, Piipari et al. 2000), the induced CYP form with AHH activity is probably CYP1B1. CYP3A5 expression is repressed by tobacco smoking in alveolar macrophages (Piipari et al. 2000). The mechanism of this repression is unknown.
No expression of PXR has been detected in human lung tissue by Northern blot analysis (Bertilsson et al. 1998, Blumberg et al. 1998, Lehmann et al. 1998). This does not exclude the possibility of expression in some specific pulmonary cell types. Extremely low levels of CAR mRNA are detected in pulmonary tissue by Northern blot after long exposure times (Baes et al. 1994). It would be of interest to clarify the possible cell specificity. The CYP inducer rifampicin induces 7-ethoxycoumarin O-deethylation (ECOD) activity in human lung microsomes of patients with tuberculosis more than 2-fold (Ohnhaus & Bluhm 1987). ECOD is catalyzed by many CYP enzymes, including CYP1A1, CYP2A6, CYP2B6, and CYP2E1, and also CYP3A to a lesser extent (Waxman et al. 1991, Yamazaki et al. 1996). It is not known which, if any, of these enzymes is induced in human lung by rifampicin.
Induction of CYP1A1 has been studied quite extensively in various human pulmonary cell lines, the most popular ones being the adenocarcinoma line A549 and the bronchioloalveolar carcinoma line NCI-H322. In general, CYP1A1 is induced by AHR agonists in pulmonary cancer cell lines (McLemore et al. 1989, Stanley et al. 1992, Vogel et al. 1994, Döhr et al. 1997, Foster et al. 1998, Urani et al. 1998, Ueng et al. 2000). In the human immortalized bronchial cell lines BEAS-2B and BEP2D, CYP1A1 mRNA is also induced by PAHs (Offord et al. 1995, Willey et al. 1996). McLemore et al. tested 24 human lung cancer cell lines for the benz(a)anthracene induction of CYP1A1 mRNA (McLemore et al. 1989). Eleven cell lines showed low-level basal CYP1A1 mRNA expression, and 16 were induced after benz(a)anthracene treatment. AHH activity correlated positively with the CYP1A1 mRNA levels. In A549 cells, transforming growth factor-β 1 repressed both basal and induced expression of CYP1A1 and CYP1B1 and basal expression of AHR, while ARNT expression was not affected (Vogel et al. 1994, Döhr et al. 1997). These repressions are dependent on protein synthesis, since the protein synthesis inhibitor cycloheximide abolished the effect of transforming growth factor-β 1 (Vogel et al. 1994, Döhr et al. 1997). In NCI-H322 cells, interferon γ decreased both basal and induced CYP1A1-related EROD activity, while interleukin-1β , tumor necrosis factor, interferon α, and interferon β were without effect (Stanley et al. 1992).
In A549 cells, CYP2B6 protein and the related PROD (pentoxyresorufin O-deethylation) activity were detected. PROD activity was not induced by phenobarbital (Foster et al. 1998). In a study with NCI-H322 cells (Stanley et al. 1992), CYP2B-, CYP2C-, and CYP3A-related 7-benzyloxyresorufin O-debenzylation (BROD) activity (Waxman et al. 1991, Gervot et al. 1999) was increased by Aroclor 1254, a mixture of polychlorinated biphenyls containing both AHR ligands and phenobarbital-like inducers (Ngui & Bandiera 1999). CYP2B6, CYP2C8, and CYP3A proteins were not detected even after Aroclor 1254 induction (Stanley et al. 1992). BROD activity was also induced by β -naphthoflavone and phenobarbital in human cultured lung slices and bronchial epithelial cells, respectively (Hoet et al. 1997, El Adlouni et al. 2000). CYP2B6 mRNA has been detected in BEAS-2B cells and CYP2E1 mRNA in BEP2D cells (Willey et al. 1996, Macé et al. 1998).
In conclusion, CYP1A1 induction in lung tissue and CYP1B1 induction in alveolar macrophages are probably mediated by the AHR/ARNT pathway, and these inductions are seen at the mRNA, protein, and catalytic activity levels. The regulation of other CYP enzymes in human lung tissue remains to be characterized.