Evidence for CYP2D6 Expression in Human Lung

Guidice, Jean‐Marc Lo; Marez, Delphine; Sabbagh, N; Legrand-Andreoletti, Maryline; Spire, Catherine; Alcaı̈de, Emmanuel; Lafitte, Jean-Jacques; Broly, Franck

doi:10.1006/bbrc.1997.7775

Cited by 48 publications

(22 citation statements)

References 20 publications

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“…To our knowledge, no other studies have reported expression of CYP2D pseudogenes in liver so far. In human lung and breast tissue, CYP2D7P expression had however been detected by RT-PCR methods (16,17,24). The fact that both types of transcripts were expressed at very similar levels demonstrates that CYP2D pseudogene expression represents an important confounding factor for CYP2D6 mRNA quantification emphasizing the necessity to use methods with adequate specificity.…”

Section: Discussionmentioning

confidence: 99%

“…A general problem for the quantitative assessment of CYP2D6 transcripts represents the possible expression of the highly homologous CYP2D7 and CYP2D8 pseudogenes which may confound the results. The presence of CYP2D7P transcripts was demonstrated in lung and breast tissue (16,17,24) whereas data for liver and other tissues are lacking.…”

mentioning

confidence: 98%

“…In two earlier studies, CYP2D6 mRNA was semiquantitatively determined in bladder mucosa and in peripheral blood mononuclear cells and found to be correlated to the debrisoquine oxidation phenotype (21,22). CYP2D6 transcripts were also detected by RT-PCR in human placenta (23) and in brain (18) and conflicting results were reported for lung (15,24). A general problem for the quantitative assessment of CYP2D6 transcripts represents the possible expression of the highly homologous CYP2D7 and CYP2D8 pseudogenes which may confound the results.…”

mentioning

confidence: 99%

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Discriminative Quantification of Cytochrome P4502D6 and 2D7/8 Pseudogene Expression by TaqMan Real-Time Reverse Transcriptase Polymerase Chain Reaction

Endrizzi

Fischer

Klein

et al. 2002

Analytical Biochemistry

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Section: Discussionmentioning

confidence: 99%

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confidence: 98%

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confidence: 99%

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Discriminative Quantification of Cytochrome P4502D6 and 2D7/8 Pseudogene Expression by TaqMan Real-Time Reverse Transcriptase Polymerase Chain Reaction

Endrizzi

Fischer

Klein

et al. 2002

Analytical Biochemistry

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“…5). CYP2D6 is predominantly expressed in liver but has been reported to be expressed also in other tissues (31,32). The CYP2D enzymes in rats are expressed both in liver and extrahepatic tissues (24,33).…”

Section: Effect Of Various Cytochrome P450 Inhibitors On the 25-hydromentioning

confidence: 99%

Porcine Microsomal Vitamin D3 25-Hydroxylase (CYP2D25)

Hosseinpour

Wikvall

2000

Journal of Biological Chemistry

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The metabolic activation of the prohormone vitamin D 3 requires a 25-hydroxylation that has been reported to be catalyzed by both mitochondrial CYP27A and a microsomal vitamin D 3 25-hydroxylase in the liver. CYP27A has been extensively studied, but its role as a physiologically important vitamin D 3 25-hydroxylase has been questioned. The present paper reports that the microsomal vitamin D 3 25-hydroxylase, purified from pig liver, converted vitamin D 3 into 25-hydroxyvitamin D 3 in substrate concentrations which are within the physiological range (apparent K m ‫؍‬ 0.1 M). The enzyme 25-hydroxylated vitamin D 3 , 1␣-hydroxyvitamin D 3 and vitamin D 2 and also converted tolterodine, a substrate for human CYP2D6, into its 5-hydroxymethyl metabolite. Tolterodine inhibited the microsomal 25-hydroxylation, whereas quinidine, an inhibitor of CYP2D6, did not markedly inhibit the reaction. The primary structure of the microsomal vitamin D 3 25-hydroxylase, designated CYP2D25, shows 77% identity with that of human CYP2D6. Northern blot and reverse transcription-polymerase chain reaction experiments revealed that CYP2D25 mRNA is expressed in higher levels in liver than in kidney and in small amounts in adrenals, brain, heart, intestine, lung, muscle, spleen, and thymus. Experiments with human liver microsomes and recombinantly expressed CYP2D6 strongly indicate that the microsomal 25-hydroxylation of vitamin D 3 in human liver is catalyzed by an enzyme different from CYP2D6.Vitamin D 3 (cholecalciferol) is essential for the absorption of calcium and phosphate in the intestine and has effects on the regulation of growth and differentiation of certain specialized cell types. The prohormone vitamin D 3 is formed from 7-dehydrocholesterol in the skin under the influence of ultraviolet irradiation. Vitamin D 3 can also be derived from dietary sources. Vitamin D 2 (ergocalciferol), which differs structurally from vitamin D 3 in the side chain, has been frequently used to treat and prevent vitamin D deficiency and is used in parenteral vitamin formulations. A cytochrome P450-dependent 25-hydroxylation in the liver is the first step in the metabolic activation of both vitamin D 3 and vitamin D 2 into their active hormonal forms. It has been reported that extracts and enzyme preparations from other tissues, e.g. kidney, also contain this activity. The 25-hydroxylation is followed by the tightly regulated 1␣-hydroxylation in the kidney, to form the biologically active compounds 1␣,25-dihydroxyvitamin D 3 and 1␣,25-dihydroxyvitamin D 2 , respectively (for review, see Ref. 1).A mitochondrial vitamin D 3 25-hydroxylase, CYP27A, 1 has been purified from several species and characterized (2-7). It is well established that this enzyme catalyzes the obligatory 27-hydroxylation of cholesterol and C 27 -sterols in bile acid biosynthesis. The tissue distribution of this mitochondrial enzyme is wide spread, its mRNA is found not only in liver but in most other tissues (3). Leading authorities in the vitamin D field have expressed skepticism ...

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“…dextromethorphan and methadone) in the liver (Eichelbaum and Gross, 1990;Gonzalez, 1996). In humans, only one isoform, CYP2D6, is expressed in various tissues including the liver, kidney, brain, placenta, breast, and lung (Niznik et al, 1990;RomkesSparks et al, 1994;Carcillo et al, 1996;Hakkola et al, 1996;Guidice et al, 1997;Huang et al, 1997). On the other hand, in rats, six isoforms (CYP2D1, CYP2D2, CYP2D3, CYP2D4, CYP2D5, and CYP2D18) have been identified by genomic analysis (Kawashima and Strobel, 1995;Gonzalez, 1996;Nelson et al, 1996).…”

mentioning

confidence: 99%

Catalytic Specificity of CYP2D Isoforms in Rat and Human

Hiroi

Chow²,

Imaoka³

et al. 2002

Drug Metab Dispos

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ABSTRACT:In rats, six cytochrome P450 (P450) 2D isoforms have been genetically identified. Nonetheless, there is little evidence of catalytic properties of each CYP2D isoform. In this study, using recombinant CYP2D isoforms (rat CYP2D1, CYP2D2, CYP2D3, and CYP2D4 and human CYP2D6) or hepatic microsomes, we investigated the catalytic specificity toward bufuralol, debrisoquine, and propranolol, which are frequently used as CYP2D substrates. Bufuralol was oxidized to three metabolites by rat and human hepatic microsomes. 1-Hydroxybufuralol was the major metabolite. 12-Ethenylbufuralol, one of the others, was identified as a novel metabolite. The formation of 1-hydroxybufuralol and 12-ethenylbufuralol in hepatic microsomes was inhibited by anti-CYP2D antibody, suggesting that these metabolites were formed by CYP2D isoforms. All rat and human recombinant CYP2D isoforms possessed activity for the 1-hydroxylation of bufuralol, indicating that this catalytic property was common to all CYP2D isoforms. However, the 12-ethenylation of bufuralol was catalyzed only by rat CYP2D4 and human CYP2D6. Debrisoquine was oxidized to two metabolites, 3-hydroxydebrisoquine, and 4-hydroxydebrisoquine, by hepatic microsomes. Recombinant CYP2D2 and CYP2D6 had very high levels of activity for the 4-hydroxylation of debrisoquine with low K m values. Only CYP2D1 had a higher level of 3-hydroxylation than 4-hydroxylation activity. Propranolol 4-hydroxylation was catalyzed by CYP2D2, CYP2D4, and CYP2D6. The 7-hydroxylation of propranolol was catalyzed only by CYP2D2. In conclusion, in rats, bufuralol 12-ethenylation activity was specific to CYP2D4 and debrisoquine 4-hydroxylation and propranolol 7-hydroxylation activities were specific to CYP2D2. These catalytic activities are useful as a probe for rat CYP2D isoforms.

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Evidence for CYP2D6 Expression in Human Lung

Cited by 48 publications

References 20 publications

Discriminative Quantification of Cytochrome P4502D6 and 2D7/8 Pseudogene Expression by TaqMan Real-Time Reverse Transcriptase Polymerase Chain Reaction

Discriminative Quantification of Cytochrome P4502D6 and 2D7/8 Pseudogene Expression by TaqMan Real-Time Reverse Transcriptase Polymerase Chain Reaction

Porcine Microsomal Vitamin D3 25-Hydroxylase (CYP2D25)

Catalytic Specificity of CYP2D Isoforms in Rat and Human

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