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

Fuhr, Uwe; Doehmer, Johannes; Battula, Narayana; Wölfel, Catherine; Flick, Ingrid; Kudla, C; Keita, Yango; Staib, A. H.

doi:10.1016/0300-483x(93)90064-y

Cited by 22 publications

(9 citation statements)

References 24 publications

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“…Caffeine biotransformation in liver has been the subject of many investigations (Berthou et al 1992;Hayes et al 1995), but intestinal caffeine metabolism on the contrary has been largely neglected until now. In vitro data suggest that CYP1A2 is the major enzyme involved in the hepatic biotransformation of caffeine to its primary metabolites parax-anthine, theobromine and theophylline (Fuhr et al 1993). Although paraxanthine formation is mediated almost exclusively by CYP1A2, CYP1A1 also seems to contribute to the formation of the two other primary caffeine metabolites, theobromine and theophylline (Fuhr et al 1993).…”

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confidence: 99%

“…In vitro data suggest that CYP1A2 is the major enzyme involved in the hepatic biotransformation of caffeine to its primary metabolites parax-anthine, theobromine and theophylline (Fuhr et al 1993). Although paraxanthine formation is mediated almost exclusively by CYP1A2, CYP1A1 also seems to contribute to the formation of the two other primary caffeine metabolites, theobromine and theophylline (Fuhr et al 1993). Finally, to evaluate the contribution of CYP1A1, CYP1A2 and other CYP enzymes to caffeine biotransformation in liver and intestine, experiments were performed with furafylline, a CYP1A2 inhibitor (Kunze & Trager 1993;Eagling et al 1998), with ketoconazole, a CYP3A inhibitor (Fitzsimmons & Collins 1997) and with a selective CYP1A1 antiserum.…”

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confidence: 99%

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Differential Activities of CYP1A Isozymes in Hepatic and Intestinal Microsomes of Control and 3‐Methylcholanthrene‐Induced Rats

Spatzenegger¹,

Horsmans

Verbeeck³

2000

Pharmacology & Toxicology

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Differences in expression of CYP1A isoforms (CYP1A1 and CYP1A2) in liver and small intestine of male Wistar rats and their inducibility by 3-methylcholanthrene as well as the effect of different CYP1A1/1A2 expression on caffeine metabolism were investigated. In rat liver, CYP1A2 is the predominant isoform and CYP1A1 protein expression in liver is significantly increased after treatment by 3-methylcholanthrene. In contrast, only CYP1A1 was detected in control and 3-methylcholanthrene induced small intestine microsomes. Treatment with 3-methylcholanthrene (40 mg/kg intraperitoneally daily during 1, 2, 3 or 4 days) demonstrated that liver CYP1A1 is more sensitive for the induction effects than CYP1A2 and also that significant induction of CYP1A1 in rat small intestine only occurred after 3 to 4 days pretreatment. Caffeine metabolism and inhibition studies by furafylline, CYP1A1 antiserum and ketoconazole revealed that the differences in the expression of CYP1A1 and CYP1A2 in the two tissues led to significant changes in the contribution of the various isoenzymes involved in the biotransformation of caffeine. Whereas in liver paraxanthine formation was almost exclusively catalyzed by CYP1A2, in rat proximal intestine it was formed by CYP1A1. In addition, other CYP enzymes (most probably CYP3A) play a significant role in theobromine and theophylline formation from caffeine in rat intestine. Overall, this study shows different expression and inducibility of CYP1A1/1A2 by 3-methylcholanthrene in rat liver and small intestine. Furthermore in rat intestine cytochrome P450 isozymes such as CYP1A1 and CYP3A replace CYP1A2 in the caffeine metabolism.The cytochrome P450s are a family of haemoproteins responsible for the metabolism of numerous substances showing their highest levels of expression in the liver (Watkins 1990). Intestinal P450 expression, especially of CYP3A, has recently been shown to contribute to the overall first-pass metabolism of some drugs (Fitzsimmons & Collins 1997). Many studies on CYP3A expression and activity in rat intestine have been performed but little is known about CYP1A expression in rat intestine and the potential correlation with its levels and activities in the liver. The CYP1A family is composed of two isoenzymes, CYP1A1 and CYP1A2. In rat, treatment with polycyclic hydrocarbons and dioxins induces CYP1A1 expression not only in the liver, but also in the small intestine (Matsuda et al. 1995). 3-Methylcholanthrene (50 mg/kg body weight intraperitoneal injection for 3 days) and tetrachlorodibenzo-p-dioxin (single intraperitoneal dose of 25 mg/kg body weight) cause nearly maximal induction of CYP1A1/1A2 proteins in liver (Dragnev et al. 1995).With regard to CYP1A1/1A2 protein levels in rat liver and intestine, different (and even contradictory) results have been reported. For instance, de Waziers et al. (1990) male Sprague-Dawley rats, whereas Zhang et al. (1996) demonstrated significant CYP1A1 and 1A2 expression in the liver of male Wistar rats, but only after induction by bnaphth...

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confidence: 99%

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confidence: 99%

Differential Activities of CYP1A Isozymes in Hepatic and Intestinal Microsomes of Control and 3‐Methylcholanthrene‐Induced Rats

Spatzenegger¹,

Horsmans

Verbeeck³

2000

Pharmacology & Toxicology

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“…P-450 IA1/IA2 are the principal isozymes involved in the metabolism of caffeine [12,13]. It was found that 17~-ethinylestradiol (EE2) had the strongest effect, while the progestogens levonorgestrel and dienogest had either only little or no effect at all on caffeine clearance.…”

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confidence: 99%

Influence of ethinylestradiol-containing combination oral contraceptives with gestodene or levonorgestrel on caffeine elimination

Balogh

Klinger

Henschel

et al. 1995

Eur J Clin Pharmacol

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In a controlled clinical trial, the elimination of caffeine was examined in 20 healthy women prior to and during one cycle of treatment with either of two oral contraceptive formulations, one containing 0.075 mg gestodene and 0.03 mg ethinylestradiol and one containing 0.125 mg levonorgestrel and 0.03 mg ethinylestradiol. In addition, caffeine clearance was determined 1 month after the last intake of the oral contraceptives. Compared with pretreatment values, the clearance of caffeine was reduced by about 54% and 55% after one treatment cycle with gestodene- and the levonorgestrel-containing oral contraceptive, respectively. Other pharmacokinetic parameters of caffeine, such as tmax and Cmax, were not affected. Clearance values returned to pretreatment values 1 month after the last administration of the oral contraceptives. There was no difference in the reduction of caffeine clearance between contraceptive formulations. A small, but significant difference in the AUC(0-24 h) values of ethinylestradiol was noted between both preparations. There was no correlation between the AUC(model) values of caffeine and the AUC(0-24 h) values of ethinylestradiol. In the present study, a somewhat more pronounced effect on the elimination of caffeine was observed than in previous investigations, where several contraceptive steroids were administered only for a period of 2 weeks.

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“…Such counter evidence may be challenged on the following grounds: (i) the failure to observe l-U following the i.v. dose of 1,3-U may have been caused by limited access of the urate to the hepatocytes; (ii) studies on isolated microsomes (7,8) and on human CYPIA2 expressed in homologous (3) and heterologous (13) cells show that the specificity ofthe cytochrome P450 system must be sensitive to, as yet, undefined parameters. For instance, CYPIA2 expressed in Chinese hamster cells has no demethylation activity with regard to theophylline as substrate (13).…”

Section: Urinary Excretion Data Relating To Theophylline Metabolismmentioning

confidence: 99%

“…dose of 1,3-U may have been caused by limited access of the urate to the hepatocytes; (ii) studies on isolated microsomes (7,8) and on human CYPIA2 expressed in homologous (3) and heterologous (13) cells show that the specificity ofthe cytochrome P450 system must be sensitive to, as yet, undefined parameters. For instance, CYPIA2 expressed in Chinese hamster cells has no demethylation activity with regard to theophylline as substrate (13). Hence failure to observe 1,3-U demethylation in vitro does not necessarily exclude 1,3-U demethylation in the intact organism; further studies on various components of the cytochrome P450 system and their in vivo specificities are called for.…”

Section: Urinary Excretion Data Relating To Theophylline Metabolismmentioning

confidence: 99%

A study on the route of 1-methylurate formation in theophylline metabolism

Bayar

Özer

1997

Eur. J. Drug Metab. Pharmacokinet.

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The urinary excretion patterns of theophylline metabolites were studied in a subject on a routine, oral dose of 600 mg/day. The highest correlation was observed between the excretions of 1,3-dimethylurate and 1-methylurate (r = 0.73 +/- 0.08). The poorest correlations were observed when the excretion of 1-methylxanthine was compared to those of 1-methylurate and 1,3-dimethylurate (r < or = 0.55, P > or = 0.05). The difference in the quality of the correlations was not due to rate-limiting or class-specific carries. The results suggested that 1-methylurate did not derive solely from 1-methylxanthine, implicating 1,3-dimethylurate as an alternative source. When the theophylline regimen was supplemented by a single dose of caffeine (4.80 mg/kg), the recovery of unaltered caffeine and the yield of metabolites arising from the primary 3-demethylation of caffeine (1-methylxanthine, 7-methylxanthine, 1-methylurate, 1,7-dimethylxanthine and 1,7-dimethylurate) were found to be unchanged. The lack of competition between caffeine and theophylline indicated that caffeine 3-demethylation and the demethylations of theophylline are not catalyzed by the same cytochrome P450 system.

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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

Cited by 22 publications

References 24 publications

Differential Activities of CYP1A Isozymes in Hepatic and Intestinal Microsomes of Control and 3‐Methylcholanthrene‐Induced Rats

Differential Activities of CYP1A Isozymes in Hepatic and Intestinal Microsomes of Control and 3‐Methylcholanthrene‐Induced Rats

Influence of ethinylestradiol-containing combination oral contraceptives with gestodene or levonorgestrel on caffeine elimination

A study on the route of 1-methylurate formation in theophylline metabolism

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