CAR and PXR expression and inducibility of CYP2B and CYP3A activities in rat and rabbit lungs

Chirulli, V.; Longo, Vincenzo; Marini, Sandra; Mazzaccaro, Arturo; Fiorio, R.; Gervasi, Pier Giovanni

doi:10.1016/j.lfs.2004.09.042

Cited by 34 publications

(29 citation statements)

References 32 publications

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“…4A). This result agrees with some previous studies showing that CAR gene does not express in mouse lungs, kidneys and brain (Choi et al 1997;Bookout et al 2006), although a very low detectable level of CAR mRNA was shown in rat lungs (Chirulli et al 2005). It is possible that constitutive expression of CYP2B genes in animal lungs is not regulated by CAR.…”

Section: Discussionsupporting

confidence: 93%

Species-specific induction of CYP2B by 2,4,6-tryphenyldioxane-1,3 (TPD)

et al. 2009

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Section: Discussionsupporting

confidence: 93%

Species-specific induction of CYP2B by 2,4,6-tryphenyldioxane-1,3 (TPD)

et al. 2009

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“…Conversely, another study showed that only tocotrienols, and not tocopherols, activated PXR in both intestinal LS180 cells and primary human hepatocytes [47]. Chirulli et al [37] have demonstrated a low level of constitutive expression of CAR mRNA, but no expression of PXR mRNA, in rat lung. These data indicate that mechanisms of xenobiotic pathway induction are tissue specific and suggest it is unlikely that α-tocopherol is modulating lung MDR1 via the PXR receptor.…”

Section: Discussionmentioning

confidence: 97%

“…In contrast to the numerous studies investigating the regulation of hepatic MDR1, regulation of lung MDR1 has received very little attention and, in a search of the literature, we were unable to find information with respect to coordinate regulation of MDR1 and CYP3A proteins in the lung. Interestingly, several agents, including clotrimazole (CLOT) and a mixture of DEX + pregnenolone 16β-carbonitrile (PCN) in rats, and rifampicin exposure in rabbits [37], which increase hepatic CYP3A protein have failed to induce lung CYP3A protein or activity levels. Unfortunately, MDR1 protein expression in either the lung or liver was not studied [37].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, several agents, including clotrimazole (CLOT) and a mixture of DEX + pregnenolone 16β-carbonitrile (PCN) in rats, and rifampicin exposure in rabbits [37], which increase hepatic CYP3A protein have failed to induce lung CYP3A protein or activity levels. Unfortunately, MDR1 protein expression in either the lung or liver was not studied [37].…”

Section: Discussionmentioning

confidence: 99%

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Regulatory mechanisms to control tissue α-tocopherol

Mustacich

Elias

et al. 2007

Free Radical Biology and Medicine

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To test the hypothesis that hepatic regulation of α-tocopherol metabolism would be sufficient to prevent over-accumulation of α-tocopherol in extrahepatic tissues and that administration of high doses of α-tocopherol would up-regulate extrahepatic xenobiotic pathways, rats received daily subcutaneous injections of either vehicle or 0.5, 1, 2, or 10 mg α-tocopherol/100 g body wt for 9 days. Liver α-tocopherol increased 15-fold in rats given 10 mg α-tocopherol/100 g body weight (mg/ 100 g) compared with controls. Hepatic α-tocopherol metabolites increased with increasing α-tocopherol doses, reaching 40-fold in rats given the highest dose. In rats injected with 10 mg/100 g, lung and duodenum α-tocopherol concentrations increased 3-fold, while α-tocopherol concentrations of other extrahepatic tissues increased 2-fold or less. With the exception of muscle, daily administration of less than 2 mg/100 g) failed to increase α-tocopherol concentrations in extrahepatic tissues. Lung cytochrome P450 3A and 1A levels were unchanged by administration of α-tocopherol at any dose. In contrast, lung P-glycoprotein (MDR-1) levels increased dose dependently and expression of this xenobiotic transport protein was correlated with lung α-tocopherol concentrations (R 2 = 0.88, P < 0.05). Increased lung MDR1 may provide protection from exposure to environmental toxins by increasing alveolar space α-tocopherol.

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“…Inhibition of BQOD BQOD is another reaction used as a marker of CYP3A in various species including pig (Nannelli et al, 2008), rat, rabbit (Chirulli et al, 2005) and fish (Smith and Wilson, 2010). In this study, KTZ was shown to be a competitive inhibitor of BQOD activity in salmon (Figure 4).…”

Section: Inhibition Patternmentioning

confidence: 64%

Comparison of three fluorescent CYP3A substrates in two vertebrate models: pig and Atlantic salmon

Žlábek¹,

Zamaratskaia²

2012

Animal

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We investigated in vitro inhibitory effects of ketoconazole (KTZ) on cytochrome P450 activity in microsomes from pigs and Atlantic salmon. The following enzymatic reactions were studied: 7-benzyloxyresorufin and 7-ethoxyresorufin O-dealkylation (BROD and EROD, respectively), 7-benzyloxy-4-trifluoromethylcoumarin O-debenzylation (BFCOD) and 7-benzyloxyquinoline O-debenzylation (BQOD). KTZ was a potent non-competitive inhibitor of BROD and BQOD in the microsomes from pigs, whereas in the microsomes from Atlantic salmon, these reactions were competitively inhibited by KTZ. BFCOD activity was inhibited by KTZ in a non-competitive manner in both species. KTZ non-competitively inhibited EROD in Atlantic salmon, but not in porcine microsomes. The activity of BROD and BQOD was higher in male than that in female pigs, but the activity of BFCOD showed no sex-related differences.

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CAR and PXR expression and inducibility of CYP2B and CYP3A activities in rat and rabbit lungs

Cited by 34 publications

References 32 publications

Species-specific induction of CYP2B by 2,4,6-tryphenyldioxane-1,3 (TPD)

Species-specific induction of CYP2B by 2,4,6-tryphenyldioxane-1,3 (TPD)

Regulatory mechanisms to control tissue α-tocopherol

Comparison of three fluorescent CYP3A substrates in two vertebrate models: pig and Atlantic salmon

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