Caffeine cytochrome

Christensen, M., G. Tybring, K. Mihara, et al. 2002. Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). Clin. Pharmacol. Ther. 71 (3) 141-152. 

Tantcheva-Poor, I., Zaigler, M., Rietbrock, S. et al. (1999). Estimation of cytochrome P450 CYP1A2 activity in 863 healthy Caucasians using a saliva-based caffeine test. Pharmacogenetics, 9, 131—44. 

Sachse C, Brockmoller J, Bauer S, Roots I. Functional significance of a C—>A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. Br J Clin Pharmacol 1999 47(4) 445—449. 

Hepatic Effects. Hepatic changes were observed in one chronic human exposure to mirex, as well as in a number of workers exposed to chlordecone for intermediate or chronic durations. In the mirex study, human subjects (sex and number not specified) from a chronically exposed cohort from southeast Ohio (route of exposure not specified, assumed to be oral) were assessed for cytochrome P- 4501A2 induction using a breath test that measures caffeine metabolism. The subjects exposed to mirex had elevated caffeine metabolism as compared to negative control individuals (subjects with no known exposure to polyhalogenated biphenyls or other related chemicals) in which the metabolism did not increase (Lambert et al. 1992). In the chlordecone study, liver function and structure in 32 men exposed to high levels of chlordecone while employed for 1-22 months (5.6... 

Hakooz N, Hamdan I (2007) Effects of dietary broccoli on human in vivo caffeine metabolism a pilot study on a group of Jordanian volunteers. Curr Drug Metab 8 9-15 Hammond DK, Bjercke RJ, Langone 11, Strobel HW (1991) Metabolism of nicotine by rat liver cytochromes P-450. Assessment utilizing monoclonal antibodies to nicotine and cotinine. Drug Metab Dispos 19 804-808... 

CYP1A2 15q22- Cytochrome P450, P450 form 4 aryl hydrocarbon Amiodarone, caffeine, dtalopram. Chronic hepatitis CP 12 P3-450 ... 

CYP2D6 22ql3.1 Cytochrome P450, Cytochrome P450, sub- Amitriptyhne, caffeine, cimetidine. Breast neoplasms. Susceptibility to CPD6 CYP2D ... 

Caffeine (3,7-dihyro-l,3,7-trimethyl-lH-purine-2,6-dione) is a natural product from tea, coffee, and other plants, and is present in many beverages and food. It is primarily metabolized in the liver by cytochrome P450 enzymes to give M-demethylated xanthine and few other metabolites (Fig. 2) [2,48 - 50]. About 17 caffeine metabolites have been identified in humans [51]. 

Walton et al. (2001a) examined data for compounds eliminated by the cytochrome P450 isoenzymes CYP1A2 in humans. Absorption, bioavailabihty, and route of excretion were generally similar between humans and the test species for each of the substances (caffeine, paraxanthine, theobromine, and theophylline). However, interspecies differences in the route of metabolism, and the enzymes involved in this process, were identified. The magnitude of difference in the internal dose, between species, showed that values for the mouse (10.6) and rat (5.4) exceeded the fourfold default factor for toxicokinetics, whereas the rabbit (2.6) and the dog (1.6) were below this value. 

Lozano, J. J., Lopez-de-Brinas, E., Centeno, N. B., Guigo, R., and Sanz, F. (1997) Three-dimensional modelling of human cytochrome P450 1A2 and its interaction with caffeine and MelQ. J. Comput. Aid. Mol. Design 11, 395-408. 

Sanz, F., Lopez-de-Brinas, E., Rodriguez, J., and Manaut, F. (1994) Theoretical study on the metabolism of caffeine by cytochrome p-450 1A2 and its inhibition. Quant. Struct.-Act. Relat. 13, 281-284. 

As with adults, the primary organ responsible for drug metabolism in children is the liver. Although the cytochrome P450 system is fully developed at birth, it functions more slowly than in adults. Phase I oxidation reactions and demethylation enzyme systems are significantly reduced at birth. However, the reductive enzyme systems approach adult levels and the methylation pathways are enhanced at birth. This often contributes to the production of different metabolites in newborns from those in adults. For example, newborns metabolize approximately 30% of theophylline to caffeine rather than to uric acid derivatives, as occurs in adults. While most phase I enzymes have reached adult levels by 6 months of age, alcohol dehydrogenase activity appears around 2 months of age and approaches adult levels only by age 5 years. 

Clozapine is principally metabolized to N -desmethylclozapine (norclozapine). It is also metabolized to and n-oxide, other hydroxyl metabolites, and a protein-reactive metabolite. The n-oxide can be converted back to clozapine. The enzyme responsible for the metabolism of clozapine to norclozapine is the cytochrome P450 1A2 enzyme (325). This is consistent with a study showing that caffeine, a marker for 1A2, is cleared in relationship to the conversion of clozapine to norclozapine ( 326). Discontinuation of coffee intake can decrease the clozapine plasma levels by more than 50%, and increasing caffeine intake can produce a reemergence of the side effects (e.g., drowsiness, excess salivation). Additionally, smoking, which induces 1A2, lowers clozapine plasma levels. Fluvoxamine, an inhibitor of 1A2, dramatically increases plasma levels, and on occasion, adverse effects are seen ( 327). This phenomenon can lead to clozapine intoxication in patients on high doses of fluvoxamine. 

Tassaneeyakul W, Mohamed Z, Birkett DJ, et al. Caffeine as a probe for human cytochromes P450 validation using cDNA-expression, immunoinhibi-tion and microsomal kinetic and inhibitor techniques. Pharmacogenetics 1992 2(4) 173-183. 

Tassaneeyakul W, Birkett DJ, McManus ME, et al. Caffeine metabolism by human hepatic cytochromes P450 contributions of 1A2, 2E1 and 3A isoforms. Biochem Pharmacol 1994 47(10) 1767-1776. 

Omeprazole can inhibit the metabolism of drugs metabolised mainly by the cytochrome P-450 enzyme subfamily 2C (diazepam, phenytoin), but not of those metabolished by subfamilies lA (caffeine, theophylline), 2D (metoprolol, propranolol), and 3A (ciclosporin, lidocaine (lignocaine), quinidine). Since relatively few drugs are metabolised mainly by 2C compared with 2D and 3A, the potential for omeprazole to interfere with the metabolism of other drugs appears to be limited, but the half lives of diazepam and phenytoin are prolonged as much as by cimetidine. 

Polybrominated Biphenyls. A recent study has used caffeine as a potential tool to characterize exposure and/or effect of PBBs (Lambert et al. 1990). In this test, caffeine is used as a metabolic probe of cytochrome P-450 isozymes activity from the CYPIA family, which in animals is significantly induced by PBBs (Safe 1984). Tire caffeine breath test (CBT) is primarily useful for detecting induction of CYP1A2 activity in human liver, and for that reason, it also has been used as a marker for exposure to PCBs, CDDs, and CDFs (Lambert et al. 1992). A volunteer population of 50 Michigan subjects with previously high serum PBB levels and 50 with undetectable or low serum levels was compared to a control population not exposed to PBBs (Lambert et al. 1992). Two tests were conducted, the CYP1A2-dependent caffeine... 

The clearances of both theophylline and caffeine are reduced in oral contraceptive users and half-lives are increased, probably because of inhibition of hepatic metabolism by cytochrome P450 (348). Caution in dosage is advisable. 

Butler MA, Iwasaki M, Guengerich FP, et al. Human cytochrome P450PA (P450IA2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines. Proc Natl Acad Sci U S A 1989 86 7696-7700. 

Wietholtz H, Voegelin M, Arnaud MJ, et al. Assessment of the cytochrome P-448 dependent liver enzyme system by a caffeine breath test. Eur J Clin Pharmacol 1981 21 53-59. 

Horsmans Y, De Koninck X, Geubel AP, et al. Microsomal function in hepatitis B surface antigen healthy carriers assessment of cytochrome P450 1A2 activity by the 14C-caffeine breath test. Pharmacol Toxicol 1995 77 247-249. 

Rost KL, Brosicke H, Brockmoller J, et al. Increase of cytochrome P450IA2 activity by omeprazole evidence by the 13C-(N-3-methyl)-caffeine breath test in poor and extensive metabolizers of S-mephenytoin. Clin Pharmacol Ther 1992 52 170-180. 

Rasmussen BB, Brosen K. Determination of urinary metabolites of caffeine for the assessment of cytochrome P4501A2, xanthine oxidase, and N-acetyltransferase activity in humans. Ther Drug Monit 1996 18 254—262. 

McQuilkin SH, Nierenberg DW, Bresnick E. Analysis of within-subject variation of caffeine metabolism when used to determine cytochrome P4501A2 and N-acetyl-transferase-2 activities. Cancer Epidemiol Biomarkers Prev 1995 4 139-146. 

For most drugs, oxidative biotransformation is performed primarily by the mixed-function oxidase enzyme system, which is present predominantly in the smooth endoplasmic reticulum of the liver. This system comprises (1) the enzyme NADPH cytochrome P450 reductase (2) cytochrome P450, a family of heme-containing proteins that catalyze a variety of oxidative and reductive reactions and (3) a phospholipid bilayer that facilitates interaction between the two proteins. Important exceptions to this rule are ethyl alcohol and caffeine, which are oxidatively metabolized by enzymes primarily present in the soluble, cytosolic fraction of the liver. 

Nordmark A, Lundgren S, Cnattingius S et al. (1999) Dietary caffeine as a probe agent for assessment of cytochrome P4501A2 activity in random urine samples. Br J Clin Pharmacol 47 397-402... 

Rasmussen BB, Bosen K (1996) Determination of urinary metabolites of caffeine for the assessment of cytochrome P4501A2, xanthine oxidase and N-acetyltransferase activity in humans. Ther Drug Monitor 18 254-262 Rostami-Hodjegan A, Nurminen S, Jackson PR, Tucker GT (1996) Caffeine urinary metabolic ratios as markers of enzyme activity a theoretical assessment. Pharmacogenetics 6 121-149... 

Sachse S, Bhambra U, Smith G et al. (2003) Polymorphisms in the cytochrome P4501A2 gene (CYP1A2) in colorectal cancer patients and control allele frequencies, linkage disequilibrium and influence on caffeine metabolism. Br J Clin Pharmacol 55 68-76... 

---