CYP1A2 is expressed along with CYP1A1 in the human lung

Wei, Cindy; Cacavale, Robert J.; Kehoe, John J.; Thomas, Paul E.; Iba, Michael M.

doi:10.1016/s0304-3835(00)00712-6

Cited by 26 publications

(25 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results were in accordance with previously published studies in different carcinoma such as head and neck cancer, lung cancer and esophageal cancer (Murray et al, 1994;Wei et al, 2001;Masood et al, 2011). CYP1A1 enzyme also showed down regulation in urinary bladder tumor and their expression correlated with bladder tumor grade (Murray et al, 1995).…”

Section: Discussionsupporting

confidence: 94%

Down-Regulation of CYP1A1 Expression in Breast Cancer

Hafeez

Ahmed²,

Rashid³

et al. 2012

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

Breast cancer is a major cause of death in women worldwide. Mammary tissue expressing xenobiotic metabolizing enzymes metabolically activate or detoxify potential genotoxic breast carcinogens. Deregulation of these xenobiotic metabolizing enzymes is considered to be a major contributory factor to breast cancer. The present study is focused on the expression of the xenobiotic metabolizing gene, CYP1A1, in breast cancer and its possible relationships with different risk factors. Twenty five tumors and twenty five control breast tissue samples were collected from patients undergoing planned surgery or biopsy from different hospitals. Semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and western-blotting were used to investigate the expression of CYP1A1 in breast cancer control and disease samples. mRNA expression of CYP1A1 was downregulated in 40% of breast tumor samples. Down-regulation was also observed at the protein level. Significnat relations were noted with marital status and tumour grade but not histopathological type. In conclusion, CYP1A1 protein expression was markedly reduced in tumor breast tissues samples as compared to paired control tissue samples.

show abstract

Section: Discussionsupporting

confidence: 94%

Down-Regulation of CYP1A1 Expression in Breast Cancer

Hafeez

Ahmed²,

Rashid³

et al. 2012

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

show abstract

“…Although recently it was shown that CYP2A13 can efficiently metabolize phenacetin and CYP2A6 has virtually no catalytic activity toward this drug (Fukami et al, 2007), phenacetin is also a CYP1A2 substrate. Because CYP1A2 can also potentially bioactivate NNK and is expressed in human lung (Wei et al, 2001), using phenacetin to assess CYP2A13 activity in human lung microsomes would also be problematic. When examining associations between individual ␣-hydroxylation metabolites and 7-hydroxycoumarin formation, a significant correlation was found between the degree of hydroxy acid formation and 7-hydroxycoumarin.…”

Section: Discussionmentioning

confidence: 99%

Analysis of CYP2A Contributions to Metabolism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone in Human Peripheral Lung Microsomes

Brown

Bedard²,

Reid³

et al. 2007

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:The objectives of this study were to determine the contributions of CYP2A13 and CYP2A6 to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism in human peripheral lung microsomes and to determine the influence of the genetic polymorphism, CYP2A13 Arg257Cys, on NNK metabolism. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), the keto-reduced metabolite of NNK, was the major metabolite produced, ranging from 0.28 to 0.9%/mg protein/min. Based on total bioactivation of NNK and NNAL by ␣-carbon hydroxylation, subjects could be classified as either high (17 subjects) or low (12 subjects) bioactivators [(5.26 ؎ 1.23) ؋ 10 ؊2 and (6.49 ؎ 5.90) ؋ 10 ؊3% total ␣-hydroxylation/mg protein/min, P < 0.05]. Similarly, for detoxification, subjects could be grouped into high (9 subjects) and low (20 subjects) categories [(2.03 ؎ 1.65) ؋ 10 ؊3 and (2.50 ؎ 3.04) ؋ 10 ؊4% total N-oxidation/mg protein/min, P < 0.05]. When examining data from all individuals, no significant correlations were found between levels of CYP2A mRNA, CYP2A enzyme activity, or CYP2A immunoinhibition and the degree of total NNK bioactivation or detoxification (P > 0.05). However, subgroups of individuals were identified for whom CYP2A13 mRNA correlated with total NNK and NNAL ␣-hydroxylation and NNAL-N-oxide formation (P < 0.05). The degree of NNAL formation and CYP2A13 mRNA was also correlated (P < 0.05). Subjects (n ‫؍‬ 84) were genotyped for the CYP2A13 Arg257Cys polymorphism, and NNK metabolism for the one variant (Arg/Cys) was similar to that for other subjects. Although results do not support CYP2A13 or CYP2A6 as predominant contributors to NNK bioactivation and detoxification in peripheral lung of all individuals, CYP2A13 may be important in some.Lung cancer is the leading cause of cancer-related death in the world, and it is estimated that cigarette smoking accounts for approximately 90% of lung cancer cases (Hecht, 2003). The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is thought to play a major role in human tobacco-related cancers (Hecht, 2003). NNK is the most prevalent pulmonary carcinogen in tobacco smoke and the most potent cancer-causing tobacco-specific nitrosamine in all animal species tested (Hecht, 1998). NNK selectively induces lung adenocarcinoma in animals (Hecht, 1998) and is believed to be a causal agent in the induction of human lung adenocarcinoma, which is now the leading form of lung cancer (Hoffmann et al., 1996;Thun et al., 1997).To induce carcinogenesis, NNK and its keto-reduced metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), require metabolic activation via ␣-carbon hydroxylation (Fig. 1). Hydroxylation of the ␣-methylene carbons of NNK and NNAL leads to the formation of DNA-methylating species, whereas hydroxylation of the ␣-methyl carbons of NNK and NNAL results in the formation of DNA-pyridyloxobutylating and -pyridylhydroxybutylating species, respectively. The formation of both types of adducts is believed to be important in the induction of ...

show abstract

“…CYP1A1 has been found in human small intestine (Vang et al, 1999;Zhang et al, 1999), occasionally with levels of ethoxyresorufin O-deethylase activity that exceed the liver (Paine et al, 1999). Native expression of CYP1A1 has been detected in human lung (Mace et al, 1998;Wei et al, 2001), in bronchial epithelial cells (Willey et al, 1996(Willey et al, , 1997, and in human placenta (Hakkola et al, 1996). It is possible, therefore, that although first-pass metabolism of debrisoquine and other "CYP2D6-specific substrates" is mediated principally by hepatic CYP2D6 with some contribution from enteric CYP1A1, the systemic metabolism of the drug may be subject to significant 4-hydroxylation by CYP1A1, both affecting the urinary metabolic ratio and contributing significantly to debrisoquine 4-hydroxylation in CYP2D6 genotypic PMs.…”

Section: Discussionmentioning

confidence: 99%

4-Hydroxylation of Debrisoquine by Human CYP1A1 and Its Inhibition by Quinidine and Quinine

Granvil

Krausz²,

Gelboin³

et al. 2002

J Pharmacol Exp Ther

View full text Add to dashboard Cite

A panel of 15 recombinant cytochromes P450 expressed in human B-lymphoblastoid cells was used to study debrisoquine 4-hydroxylation. Both CYP2D6 and CYP1A1 carried out the reaction. The apparent K m (micromolar) and V max (picomoles per minute per picomole of P450) for CYP2D6 were 12.1 and 18.2 and for CYP1A1 were 23.1 and 15.2, respectively. CYP1A1 debrisoquine 4-hydroxylase was inhibited by the CYP1A1 inhibitor ␣-naphthoflavone and the CYP1A1 substrate 7-ethoxyresorufin. Additionally and surprisingly, this reaction was also inhibited by quinidine and quinine, with respective IC 50 values of 1.38 Ϯ 0.10 and 3.31 Ϯ 0.14 M, compared with those for CYP2D6 debrisoquine 4-hydroxylase of 0.018 Ϯ 0.05 and 3.75 Ϯ 2.07 M, respectively. Anti-CYP1A1 monoclonal antibody (mAb) 1-7-1 abolished CYP1A1 debrisoquine hydroxylase and anti-CYP2D6 mAb 50-1-3 eradicated CYP2D6 debrisoquine 4-hydroxylase. Three further CYP2D6-specific reactions were tested: dextromethorphan O-demethylation, bufuralol 1Ј-hydroxylation, and sparteine dehydrogenation. The CYP2D6 specificity, judged by the CYP2D6/CYP1A1 activity ratios was 18.5, 7.0, 6.0, and 1.6 for dextromethorphan, bufuralol, sparteine, and debrisoquine, respectively. Thus, debrisoquine is not a specific CYP2D6 substrate and quinidine is not a specific CYP2D6 inhibitor. These findings have significant implications for the conduct of in vitro drug metabolism inhibition studies and underscore the fallacy of "specific chemical inhibitors" of a supergene family of enzymes that have overlapping substrate specificities. The use of highly specific mAbs in such studies is mandated. It is unclear as yet whether these findings have implications for the relationship between CYP2D6 genotype and in vivo debrisoquine 4-hydroxylase activity.

show abstract

CYP1A2 is expressed along with CYP1A1 in the human lung

Cited by 26 publications

References 33 publications

Down-Regulation of CYP1A1 Expression in Breast Cancer

Down-Regulation of CYP1A1 Expression in Breast Cancer

Analysis of CYP2A Contributions to Metabolism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone in Human Peripheral Lung Microsomes

4-Hydroxylation of Debrisoquine by Human CYP1A1 and Its Inhibition by Quinidine and Quinine

Contact Info

Product

Resources

About