Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: KEGG:D06103 (Theophylline)
 2,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primary steps in the metabolism of caffeine and theophylline are cleavage of methyl groups and/or hydroxylation at position 8, mediated by cytochromes P450. V79 Chinese hamster cells genetically engineered for stable expression of single forms of rat cytochromes P450IA1, P450IA2 and P450IIBI and human P450IA2 and rat liver epithelial cells expressing murine P450IA2 were used to overcome problems arising in the proper allocation of metabolic pathways to specific isoforms by conventional techniques. These cell lines were exposed to caffeine and/or theophylline, and concentrations of metabolites formed in the medium were determined by HPLC. Caffeine was metabolized by human, rat and murine P450IA2, resulting in the formation of four primary demethylated and hydroxylated metabolites. However, there were differences in the relative amounts of the metabolites. The human and the mouse P450IA2 isoforms predominantly mediated 3-demethylation of caffeine. The rat cytochrome P450IA2 mediated both 3-demethylation and 1-demethylation of caffeine to a similar extent. Theophylline was metabolized mainly via 8-hydroxylation. All cell lines tested were able to carry out this reaction, with highest activities in cell lines expressing rat or human P450IA2, or rat P450IA1. These results support the hypothesis that caffeine plasma clearance is a specific in vivo probe for determining human P450IA2 activity.
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PMID:Biotransformation of caffeine and theophylline in mammalian cell lines genetically engineered for expression of single cytochrome P450 isoforms. 173 11

Theophylline metabolism has been studied in a reconstituted monooxygenase system with purified forms of cytochrome P-450: P-450a, P-450b, P-450d and P-450k as well as in liver microsomes of control and 3-methylcholanthrene-induced rats. Cytochrome P-450 isoforms, P-450a and P-450b, had no effect on theophylline metabolism, whereas forms P-450d and P-450k induced the synthesis of 1.3-dimethyluric acid (1.3-DMA) at the rates of 900 and 330 pmol/min/nmol of protein, respectively. The catalytic activity of these isoforms was fully inhibited by homologous monospecific antibodies. P-450c catalyzed the formation of a nonidentified metabolite. In microsomes of control animals antibodies specifically directed to cytochrome P-450k suppressed the rate of 1.3-DMA synthesis by 73%, whereas antibodies specifically raised against P-450c+d--by 11%. In microsomes of methylcholanthrene-induced animals the rate of 1.3-DMA synthesis was increased two-fold. This activity was inhibited by 61% by antibodies to cytochrome P-450k and by 18% by anti-P-450c+d antibodies.
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PMID:[Theophylline metabolism by rat liver microsomal monooxygenases]. 207 25

Theophylline kinetics, as an in vivo probe for the potentially toxic cytochrome P-450I pathway of drug metabolism, were studied in 11 healthy volunteers and 11 patients with calcific chronic pancreatitis at Madras, South India. Theophylline clearance was faster in the patients than controls [median 69 (range 39-114) vs 45 (33-56) ml h-1 kg-1, p = 0.003]. In keeping with this finding, detailed social histories identified a higher exposure level in the patients to xenobiotics that are inducers of cytochrome P-450I and/or yield reactive metabolites upon processing thereby (score 7, 4-11 vs 3, 2-9, p = 0.002). However, the concentration of D-glucaric acid in urine, as a marker of phase II conjugating pathways of drug metabolism, was similar in patients and controls. This pattern of drug metabolism could predispose to oxidant stress: hence micronutrient antioxidant supplements may have therapeutic (or even prophylactic) value in tropical chronic pancreatitis.
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PMID:Evidence for induction of cytochrome P-450I in patients with tropical chronic pancreatitis. 237 24

V79 Chinese hamster cells genetically engineered for stable expression of single forms of rat cytochromes P450IA1, P450IA2, P450IIB1, human P450IA2, and rat liver epithelial cells expressing murine P450IA2 were used to allocate metabolic pathways of methylxanthines to specific isoforms and to test the suitability of such cell lines for investigations on drug interactions occurring at the cytochrome expressed. The cell lines were exposed to caffeine and/or theophylline and concentrations of metabolites formed in the medium were determined by HPLC. Caffeine was metabolized by human, rat and murine P450IA2, resulting in the formation of four primary demethylated and hydroxylated metabolites. However, there were differences in the relative amounts of the metabolites. The human and the mouse P450IA2 isoforms predominantly mediated 3-demethylation of caffeine. The rat cytochrome P450IA2 mediated both 3-demethylation and 1-demethylation of caffeine to a similar extent. The results support the hypothesis that caffeine plasma clearance is a specific in vivo probe for determining human P450IA2 activity. Addition of the quinolone antibiotic agents pipemidic acid or pefloxacin, both known to inhibit caffeine metabolism in vivo and in human liver microsomes, reduced formation rates of all metabolites of caffeine in cells expressing rat and human P450IA2. Theophylline was mainly metabolized via 8-hydroxylation. All cell lines tested were able to carry out this reaction, with highest activities in cell lines expressing rat or human P450IA2, or rat P450IA1.
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PMID:Biotransformation of methylxanthines in mammalian cell lines genetically engineered for expression of single cytochrome P450 isoforms. Allocation of metabolic pathways to isoforms and inhibitory effects of quinolones. 823 73

Theophylline is predominantly metabolized by cytochrome P4501A2 (CYP1A2). A possible interaction between griseofulvin and theophylline was reported to our laboratory, which led us to form the hypothesis that griseofulvin induces the metabolism of theophylline. One purpose of this study was to investigate this hypothesis. The study was carried out as a randomized crossover study of 12 healthy volunteers. In period A of the study, each volunteer received a single dose of 300 mg theophylline ethylenediamine orally. In period B, the subjects took fluvoxamine, 50 mg for 1 day and 100 mg for 6 days, and on day 4, the subjects ingested 300 mg theophylline ethylenediamine. Fluvoxamine is a potent inhibitor of CYP1A2, and period B was included as a positive control. In period C, the subjects took 500 mg griseofulvin for 9 days; on day 8 the subjects again ingested 300 mg theophylline ethylenediamine. Theophylline and its metabolites (1-methyluric acid [IMU], 3-methylxanthine [3MX], and 1,3-dimethyluric acid [13DMU]) in plasma and urine were assayed by high-performance liquid chromatography. During fluvoxamine intake, the median of the total clearance of theophylline decreased from 80 ml/min to 24 ml/min, and the half-life increased from 6.6 to 22 h. The partial formation clearances of the metabolites decreased from 17 to 1.7 ml/min, from 8.9 to 0.9 ml/min, and from 21 to 6.8 ml/min for 1MU, 3MX, and 13DMU, respectively. The results confirm that assessment of theophylline metabolism indeed serves as a biomarker for CYP1A2. During griseofulvin ingestion, the median of the total and partial clearances of theophylline were 84 ml/min, 22 ml/min (1MU), 9.4 ml/min (3MX), and 25 ml/min (13DMU). The half-life decreased significantly from 6.6 to 5.7 h. The increase in partial formation clearances of 1MU and 13DMU, but not of 3MX, were statistically significant. The increase in the total clearance reached only borderline significance. In four subjects a marked induction was seen for all pharmacokinetic parameters, suggesting that the susceptibility to induction is more pronounced in some subjects. This susceptibility could theoretically be explained by a polymorphism in the inducibility of the gene coding for the CYP1A2 enzyme.
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PMID:Griseofulvin and fluvoxamine interactions with the metabolism of theophylline. 902 48

Theophylline is a drug used in the treatment of obstructive pulmonary disease and a strong immunomodulator and has anti-inflammatory potential. However, its mechanism of definite action is still poorly defined. In the present study the effect of teophylline on the in vitro formation and release of reactive oxygen species in polymorphonuclear neutrophils (PMN) was studied at concentration of 0.9-130 microg/ml. The neutrophils oxygen metabolism was assessed with methods: luminol-dependent chemiluminescence, cytochrome C reduction, phenol red oxidation, and Griess reaction. In vitro theophylline treatment most effectively inhibit neutrophil hydrogen peroxide and nitric oxide generation (at 90 and 130 microg/ml), superoxide production (at 1.3 microg/ml), and diminish chemiluminescence (at the smallest concentrations 0.9 and 1.3 microg/m). We concluded that the effects of theophylline on granulocyte function are likely to contribute to the drug's clinical efficacy.
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PMID:[The influence of theophilline on oxygen metabolism of neutrophils in vitro]. 1567 67