Induction of hepatic CYP1A2 by the oral administration of caffeine to rats: lack of association with the Ah locus

Abstract

Caffeine was administered to male Wistar albino rats for two weeks at three concentrations, namely 0.1, 0.2 and 0.3%, and hepatic cytochrome P450-dependent mixed-function oxidase determined. Caffeine administration gave rise to a marked, dose-dependent increase in the O-deethylation of ethoxyresorufin and, to a lesser extent, in the O-depentylation of pentoxyresorufin. Erythromycin N-demethylase, p-nitrophenol hydroxylase and lauric acid hydroxylase activities, as well as total cytochrome P450 content were unaffected by this treatment. Immunoblot analysis revealed that caffeine gave rise to a dose-dependent increase in the hepatic CYP1A2, and at the highest dose only, CYP2B apoprotein levels. Apoprotein levels of CYP3A and CYP2E1 were not modulated by the treatment with caffeine at all dose levels studied. Caffeine could not displace [3H]TCDD from the rat hepatic cytosolic Ah receptor. Computer analysis showed that caffeine is essentially a planar molecule with an area/depth ratio 4.8, characteristic of CYP1A substrates/inducers. Molecular modelling revealed that the caffeine molecule could orientate itself within the putative CYP1A2 active site so as to facilitate demethylation of the N-1, N-3 and N-7 positions. However, at physiological pH, the N-9 nitrogen atom is likely to be partially protonated, allowing it to participate in an electrostatic interaction with the negatively-charged glutamate 318-residue, favouring N-3 demethylation, the major pathway of metabolism in both humans and animals. In conclusion caffeine, being essentially planar, is an inducer of CYP1A2 in rat liver.

Short-term black tea intake modulates the excretion of urinary mutagens in rats treated with 2-amino-3-methylimidazo-[4,5-f]quinoline (IQ): role of CYP1A2 upregulation

“…No such effect was observed when decaffeinated tea was employed, but was restored when decaffeinated tea was supplemented with the normal amount of caffeine, indicating that the xanthine is largely responsible for this effect, and may be associated with the documented upregulation of the cytochrome P450 enzyme CYP1A2 by caffeine, so modulating the metabolic pathways of the carcinogen (Ayalogu et al 1995;Bu-Abbas et al 1999a;Chen et al 1996). Subsequently, metabolic studies revealed that treatment of rats with green tea for 6 weeks led to an increase in the excretion of the N-glucuronide of Nhydroxy-IQ, a detoxication product, and, moreover, the same treatment stimulated the excretion of IQ in the form of the inactive 5-hydroxy-IQ, present in the urine in the form of conjugates, indicating an overall shift of the metabolism towards the detoxication (Embola et al 2001a(Embola et al , 2001b.…”

Up-regulation of the CYP1 family in rat and human liver by the aliphatic isothiocyanates erucin and sulforaphane

“…Erucin and sulforaphane, both small molecular weight aliphatic compounds, are clearly strong inducers of CYP1 family expression despite the fact that structurally they are unlikely to be Ah receptor agonists. However, it should be borne in mind that up-regulation of the CYP1 family, independent of binding to the Ah receptor, has been reported (Ayalogu et al, 1995;Boyd et al, 1995;Lesca et al, 1995).…”

Effects of Repeated Green Tea Catechin Administration on Human Cytochrome P450 Activity

“…However, the modulation effect observed in preclinical studies could be attributed to caffeine present in green tea because caffeine has been shown to be a potent inducer of CYP1A2 (21,22). This may explain the lack of clinical effect on human CYP1A2 activity observed in our study because Polyphenon E is a decaffeinated green tea catechin product.…”