Human cytochrome P-450PA (P-450IA2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines.

Butler, Mary Ann; Iwasaki, M.; Guengerich, F. Peter; Kadlubar, Fred F.

doi:10.1073/pnas.86.20.7696

Cited by 564 publications

(351 citation statements)

References 36 publications

(45 reference statements)

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“…This has been shown in a GWAS of blood metabolites and of caffeine metabolites 27, 28. Caffeine is metabolized primarily by the enzyme CYP1A2 29, but does not inhibit nicotine pharmacokinetics in‐vivo nor does it alter cigarette consumption 25, 30. For example, when given caffeine at a high dose (12 mg/kg/day, approximately 800 mg per person, relative to average daily consumption of 200 mg) there was no effect on nicotine or cotinine plasma levels or on nicotine intake, cigarettes smoked or grams of tobacco burned 23; therefore, caffeine was not investigated further as a potential CYP2A6 inhibitor.…”

Section: Discussionmentioning

confidence: 87%

Does coffee consumption impact on heaviness of smoking?

et al. 2017

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Background and AimsCoffee consumption and cigarette smoking are strongly associated, but whether this association is causal remains unclear. We sought to: (1) determine whether coffee consumption influences cigarette smoking causally, (2) estimate the magnitude of any association and (3) explore potential mechanisms.DesignWe used Mendelian randomization (MR) analyses of observational data, using publicly available summarized data from the Tobacco and Genetics (TAG) consortium, individual‐level data from the UK Biobank and in‐vitro experiments of candidate compounds.SettingThe TAG consortium includes data from studies in several countries. The UK Biobank includes data from men and women recruited across England, Wales and Scotland.ParticipantsThe TAG consortium provided data on n ≤ 38 181 participants. The UK Biobank provided data on 8072 participants.MeasurementsIn MR analyses, the exposure was coffee consumption (cups/day) and the outcome was heaviness of smoking (cigarettes/day). In our in‐vitro experiments we assessed the effect of caffeic acid, quercetin and p‐coumaric acid on the rate of nicotine metabolism in human liver microsomes and cDNA‐expressed human CYP2A6.FindingsTwo‐sample MR analyses of TAG consortium data indicated that heavier coffee consumption might lead to reduced heaviness of smoking [beta = −1.49, 95% confidence interval (CI) = −2.88 to −0.09]. However, in‐vitro experiments found that the compounds investigated are unlikely to inhibit significantly the rate of nicotine metabolism following coffee consumption. Further MR analyses in UK Biobank found no evidence of a causal relationship between coffee consumption and heaviness of smoking (beta = 0.20, 95% CI = –1.72 to 2.12).ConclusionsAmount of coffee consumption is unlikely to have a major causal impact upon amount of cigarette smoking. If it does influence smoking, this is not likely to operate via effects of caffeic acid, quercetin or p‐coumaric acid on nicotine metabolism. The observational association between coffee consumption and cigarette smoking may be due to smoking impacting on coffee consumption or confounding.

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Section: Discussionmentioning

confidence: 87%

Does coffee consumption impact on heaviness of smoking?

et al. 2017

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“…The maturation of CYP1A2 was delayed compared to other cytochrome P450 isoforms (Cresteil 1998;Sonnier & Cresteil 1998). Using caffeine N-3-demethylation in vitro as a marker for CYP1A2 (Butler et al 1989), Cazeneuve et al (1994) similarly showed a rise in CYP1A2 activity during this period, reaching a plateau at around 120 days.…”

Section: Cytochrome P450 In the Neonatal Human Livermentioning

confidence: 92%

Neonatal Hepatic Drug Elimination

Gow

Ghabrial

Smallwood

et al. 2001

Pharmacology & Toxicology

102

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After the transition from in utero to newborn life, the neonate becomes solely reliant upon its own drug clearance processes to metabolise xenobiotics. Whilst most studies of neonatal hepatic drug elimination have focussed upon in vitro expression and activities of drug-metabolising enzymes, the rapid physiological changes in the early neonatal period of life also need to be considered. There are dramatic changes in neonatal liver blood flow and hepatic oxygenation due to the loss of the umbilical blood supply, the increasing portal vein blood flow, and the gradual closure of the ductus venosus shunt during the first week of life. These changes which may well affect the capacity of neonatal hepatic drug metabolism. The hepatic expression of cytochromes P450 1A2, 2C, 2D6, 2E1 and 3A4 develop at different rates in the postnatal period, whilst 3A7 expression diminishes. Hepatic glucuronidation in the human neonate is relatively immature at birth, which contrasts with the considerably more mature neonatal hepatic sulfation activity. Limited in vivo studies show that the human neonate can significantly metabolise xenobiotics but clearance is considerably less compared with the older infant and adult. The neonatal population included in pharmacological studies is highly heterogeneous with respect to age, body weight, ductus venosus closure and disease processes, making it difficult to interpret data arising from human neonatal studies. Studies in the perfused foetal and neonatal sheep liver have demonstrated how the oxidative and conjugative hepatic elimination of drugs by the intact organ is significantly increased during the first week of life, highlighting that future studies will need to consider the profound physiological changes that may influence neonatal hepatic drug elimination shortly after birth.The development of clinical pharmacology has resulted in a more rational approach to drug therapy, as well as a deeper understanding of the factors capable of influencing drug disposition, and hence drug effects. Of these factors, age is of great importance. However, substantial differences in drug disposition not only exist between neonates and adults, but also among premature neonates, term neonates, infants and children.During the last two decades drug disposition in the neonatal period has been studied extensively. A major impetus for these studies seems to have been a series of incidents involving illness or death following the administration of drugs at ratios of dose/body weight innocuous in an adult (Craft et al. 1974;Gershanik et al. 1982). These studies have shown that the transition from neonate to childhood is characterised by the ontogeny of all of the processes of drug absorption, distribution, hepatic metabolism and renal excretion, with the development of hepatic drug metabolism being particularly important.The extent to which the neonatal drug-metabolising en-

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“…CYP1A2 is of toxicological importance because it metabolizes several drugs and carcinogens (Butler et al, 1989). The gene seems to be dispensable since CYP1A2 knock-out mice are viable and fertile (Liang et al, 1996).…”

Section: Commentsmentioning

confidence: 99%