Caffeine metabolism by human hepatic cytochromes p450: Contributions of 1A2, 2E1 and 3A isoforms

Tassaneeyakul, Wichittra; Birkett, Donald; McManus, Michael E.; Tassaneeyakul, Wongwiwat; Veronese, Maurice E.; Andersson, Tommy; Tukey, Robert H.; Miners, John O.

doi:10.1016/0006-2952(94)90304-2

Cited by 185 publications

(119 citation statements)

References 16 publications

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“…To our knowledge, the P. putida CBB5 methylxanthine Ndm provides the first concrete example of a Rieske non-haem iron oxygenase with broadbased N-demethylase activity on a number of purine alkaloids. N-Demethylation (or N-dealkylation) reactions in eukaryotes and prokaryotes are known to be catalysed only by cytochrome P450s (Abel et al, 2003;Asha & Vidyavathi, 2009;Caubet et al, 2004;Cha et al, 2001;Guengerich, 2001;Tassaneeyakul et al, 1994), various flavo-enzymes (Chang et al, 2007;Kvalnes-Krick & Jorns, 1986;Meskys et al, 2001;Nishiya & Imanaka, 1993;Phillips et al, 1998;Shi et al, 2004;Wagner, 1982) and a ketoglutarate-dependent non-haem iron oxygenase (Tsukada et al, 2006). This study therefore broadens our understanding of the possible enzymic mechanism for N-demethylation and will aid the discovery of new microbial N-demethylases in the future.…”

Section: Discussionmentioning

confidence: 76%

Characterization of a broad-specificity non-haem iron N-demethylase from Pseudomonas putida CBB5 capable of utilizing several purine alkaloids as sole carbon and nitrogen source

Summers

Louie

et al. 2011

Microbiology

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N-Demethylation of many xenobiotics and naturally occurring purine alkaloids such as caffeine and theobromine is primarily catalysed in higher organisms, ranging from fungi to mammals, by the well-studied membrane-associated cytochrome P450s. In contrast, there is no well-characterized enzyme for N-demethylation of purine alkaloids from bacteria, despite several reports on their utilization as sole source of carbon and nitrogen. Here, we provide what we believe to be the first detailed characterization of a purified N-demethylase from Pseudomonas putida CBB5. The soluble N-demethylase holoenzyme is composed of two components, a reductase component with cytochrome c reductase activity (Ccr) and a two-subunit N-demethylase component (Ndm). Ndm, with a native molecular mass of 240 kDa, is composed of NdmA (40 kDa) and NdmB (35 kDa). Ccr transfers reducing equivalents from NAD(P)H to Ndm, which catalyses an oxygen-dependent N-demethylation of methylxanthines to xanthine, formaldehyde and water. Paraxanthine and 7-methylxanthine were determined to be the best substrates, with apparent K m and kcat values of 50.4±6.8 μM and 16.2±0.6 min−1, and 63.8±7.5 μM and 94.8±3.0 min−1, respectively. Ndm also displayed activity towards caffeine, theobromine, theophylline and 3-methylxanthine, all of which are growth substrates for this organism. Ndm was deduced to be a Rieske [2Fe–2S]-domain-containing non-haem iron oxygenase based on (i) its distinct absorption spectrum and (ii) significant identity of the N-terminal sequences of NdmA and NdmB with the gene product of an uncharacterized caffeine demethylase in P. putida IF-3 and a hypothetical protein in Janthinobacterium sp. Marseille, both predicted to be Rieske non-haem iron oxygenases.

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Section: Discussionmentioning

confidence: 76%

Characterization of a broad-specificity non-haem iron N-demethylase from Pseudomonas putida CBB5 capable of utilizing several purine alkaloids as sole carbon and nitrogen source

Summers

Louie

et al. 2011

Microbiology

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“…These substrates include industrial solvents such as benzene, toluene, aniline, and halogenated solvents (18); alcohols such as ethanol (19), glycerol, phenol, and p-nitrophenol (20); and bicyclic heterocycles such as caffeine (21) and the muscle relaxant chlorzoxazone (22). However, CYP2E1 is also known to metabolize endogenous fatty acids, including lipids associated with signaling mechanisms such as arachidonic acid (23) and epoxyeicosatrienoic acids (24).…”

mentioning

confidence: 99%

Structures of Human Cytochrome P-450 2E1

Porubsky¹,

Meneely²,

Scott

2008

Journal of Biological Chemistry

191

102

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Human microsomal cytochrome P-450 2E1 (CYP2E1) monooxygenates >70 low molecular weight xenobiotic compounds, as well as much larger endogenous fatty acid signaling molecules such as arachidonic acid. In the process, CYP2E1 can generate toxic or carcinogenic compounds, as occurs with acetaminophen overdose, nitrosamines in cigarette smoke, and reactive oxygen species from uncoupled catalysis. Thus, the diverse roles that CYP2E1 has in normal physiology, toxicity, and drug metabolism are related to its ability to metabolize diverse classes of ligands, but the structural basis for this was previously unknown. Structures of human CYP2E1 have been solved to 2.2 Å for an indazole complex and 2.6 Å for a 4-methylpyrazole complex. Both inhibitors bind to the heme iron and hydrogen bond to Thr 303 within the active site. Complementing its small molecular weight substrates, the hydrophobic CYP2E1 active site is the smallest yet observed for a human cytochrome P-450. The CYP2E1 active site also has two adjacent voids: one enclosed above the I helix and the other forming a channel to the protein surface. Minor repositioning of the Phe 478 aromatic ring that separates the active site and access channel would allow the carboxylate of fatty acid substrates to interact with conserved 216 QXXNN 220 residues in the access channel while positioning the hydrocarbon terminus in the active site, consistent with experimentally observed -1 hydroxylation of saturated fatty acids. Thus, these structures provide insights into the ability of CYP2E1 to effectively bind and metabolize both small molecule substrates and fatty acids.Cytochrome P-450 (P-450) 3 is a superfamily of enzymes involved in monooxygenation of both endogenous and exogenous substrates. A subset of these enzymes, including cytochrome P-450 2E1 (CYP2E1), are known for their role in the clearance of drugs and other xenobiotics by introducing or unmasking sites for subsequent conjugation and elimination from the body. From a biochemical standpoint these enzymes are fascinating for the diversity of substrates each xenobioticmetabolizing P-450 can metabolize, yet often with exquisite selectivity in the metabolites generated. Unfortunately, in the process some P-450-mediated metabolism can produce toxic or carcinogenic products. Among cytochrome P-450 enzymes, CYP2E1 is particularly notable for this ability and the resulting toxicity (1). This activity is most substantial in the liver because CYP2E1 comprises over 50% of the hepatic cytochrome P-450 mRNA (2) and 7% of the hepatic cytochrome P-450 protein (3). However, CYP2E1 is also expressed at lower levels in a variety of extrahepatic tissues (4), where it is thought to play a role in the metabolism of important endogenous molecules. CYP2E1 levels and the resulting toxicity varies markedly in response to alcohol consumption (5), diabetes (6), obesity (7), and fasting (8). Thus, the action of CYP2E1 can have a significant influence on human health and drug metabolism.CYP2E1 has been connected with liver toxicity through two ...

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“…Our knowledge about the enzymology of caffeine metabolism in man (Table 40) has increased during recent years (Kalow, 1985;Berthou et al, 1988Berthou et al, , 1991Butler et al, 1989;Fuh et al, 1992;Tassaneeyakul et al, 1994;Chung and Cha, 1997). CYP1A2 is the most essential enzyme in the metabolism of caffeine, although other CYP enzymes, flavin monooxygenase, and N-acetyltransferase are also involved in its metabolism (Kalow, 1985;Butler et al, 1989;Berthou et al, 1991;Fuh et al, 1992;Tassaneeyakul et al, 1994;Chung and Cha, 1997).…”

Section: Metabolism In the Adult Human Beingmentioning

confidence: 99%

“…CYP1A2 is the most essential enzyme in the metabolism of caffeine, although other CYP enzymes, flavin monooxygenase, and N-acetyltransferase are also involved in its metabolism (Kalow, 1985;Butler et al, 1989;Berthou et al, 1991;Fuh et al, 1992;Tassaneeyakul et al, 1994;Chung and Cha, 1997). The role of CYP1A2 has been nicely demonstrated with CYP1A2 deficient knockout mice, whose half-life of caffeine is seven times longer, and whose metabolic pattern of caffeine is changed compared to mice expressing the CYP1A2 enzyme in the normal manner (Buters et al, 1996).…”

Section: Metabolism In the Adult Human Beingmentioning

confidence: 99%

Intake of caffeine and other methylxanthines during pregnancy and risk for adverse effects in pregnant women and their foetuses

Andersson¹,

Hallström²,

Kihlman³

2005

TemaNord

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Caffeine metabolism by human hepatic cytochromes p450: Contributions of 1A2, 2E1 and 3A isoforms

Cited by 185 publications

References 16 publications

Characterization of a broad-specificity non-haem iron N-demethylase from Pseudomonas putida CBB5 capable of utilizing several purine alkaloids as sole carbon and nitrogen source

Characterization of a broad-specificity non-haem iron N-demethylase from Pseudomonas putida CBB5 capable of utilizing several purine alkaloids as sole carbon and nitrogen source

Structures of Human Cytochrome P-450 2E1

Intake of caffeine and other methylxanthines during pregnancy and risk for adverse effects in pregnant women and their foetuses

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