茶叶生物碱的生物合成与代谢的研究进展

茶叶中的生物碱类化合物不仅含量高,而且生物活性强、作用广泛,是该植物作为嗜好饮料的重要物质基础之一。本文综述了近年来人们对咖啡因、茶碱、可可碱及theacrine等甲基黄嘌呤类生物碱在茶叶植物中的分布、生物合成、代谢途径、相应的生物转化和分析检测方法等方面的研究成果,并对茶叶的植物化学、基因克隆和遗传育种等方面的问题进行了探讨和展望。     

Behavioral and biochemical consequences of perinatal exposure of mice to instant coffee: A correlative evaluation

In the present study, the lasting effects of prepartum and perinatally consumed instant coffee by female mice on the behavior as well as on the level of activities of certain enzymes in the tissues of their male offspring have been investigated. The behavioral observations of nonsocial investigation, defense, displacement, latency to threat and naso-nasal contact has decreased significantly in offspring of treated mothers, while the threat, attack, latency to threat and attack and number of fights have increased significantly. Hence, coffee has proven to be an inducer of hyperactive behavior in these offspring. Such effects are both dose dependent and duration-of-treatment dependent. Moreover, variations were detected in the level of AChE activity in the brain tissues of these offspring together with variations in the levels of AcPase and AlPase activities in their liver, kidneys and testes. Such variations in these organs have developed in utero, making these enzymes convenient markers in teratological studies.     

Chronic haloperidol treatment leads to an increase in the intramembrane interaction between adenosine A2 and dopamine D2 receptors in the neostriatum

Stimulation of adenosine A₂ receptors (with the selective adenosine A₂ agonist CGS 21680) in rat striatal membrane preparations, produces a decrease in both the affinity of D₂ receptors and the transduction of the signal from the D₂ receptor to the G protein. This intramembrane A₂-D₂ interaction might be responsible for the behavioural depressant effects of adenosine agonists and for the behavioural stimulant effects of adenosine antagonists such as caffeine and theophylline. Dopamine denervation induces an increase in the intramembrane A₂-D₂ interaction, which may underlie the observed higher sensitivity to the behavioural effects induced by adenosine antagonists found in these animals. The present study was designed to examine if chronic treatment with haloperidol, which also produces dopamine receptor supersensitivity, is also associated with an increase in the intramembrane A₂-D₂ interaction in the neostriatum and with a higher sensitivity to the behavioural effects induced by adenosine antagonists. The data showed that: (i) haloperidol pretreatment causes a higher binding of the D₂ antagonist [³H] raclopride in striatal membrane preparations due to an increase in the number of D₂ receptors without changes in their affinity for the antagonist (increase in B_max without changes in k_d); (ii) GCS 21680 decreases the affinity of dopamine for the D₂ receptor, by increasing the equilibrium dissociation constants of high (K_h) and low affinity (K₁) dopamine D₂ binding sites and increases the proportion of high affinity binding sites (R_h); (iii) a low dose of CGS 21680 (3 nM), which is ineffective in membrane preparations from neostriatum of nontreated animals, is effective in membranes from the striatum of haloperidol-pretreated animals; (iv) the nonselective adenosine antagonist theophylline (20 mg/kg SC) causes a higher motor activation in rats pretreated with haloperidol. The possible relevance of these results for the pathophysiology and treatment of tardive dyskinesias is discussed.     

Aminophylline shortens thiopental sleep-time and enhances noradrenergic neurotransmission in rats

We investigated the effect of aminophylline on thiopental sleep-times and monoamine neurotransmitter turnover rates in discrete brain areas. Aminophylline-treated rats had shorter thiopental sleep-times than saline-treated controls. Noradrenergic neurotransmission was greater following aminophylline treatment in thiopental-anesthetized rats in all brain areas while turnover in other monoaminergic pathways was unchanged. These data suggest that acute aminophylline treatment increases central noradrenergic neurotransmission which pharmacodynamically diminishes the hypnotic response to thiopental.     

Slow Ca2+ and Na+ responses induced by isoproterenol and methylxanthines in isolated perfused guinea pig hearts exposed to elevated K+.

The induction of Ca²⁺ channels in cardiac muscles by catecholamines (CA) was studied in a physiological preparation, the isolated perfused guinea pig heart. The heart was rendered inexcitable by elevating external [K⁺] to 27 mm, which depolarizes the cells to about ?40 mV. Isoproterenol (10^?7m) infusion induced excitability within 1 min, i.e., slowlyrising electrical potentials with concomitant contraction in response to stimulation. Their shape and duration was similar to that of the plateau component of the normal action potential, but their maximum rate of rise was only 6 to 12 V/s. The slow responses persisted for over 2 h. Methylxanthines (MX) (caffeine and theophylline, 3 mm) mimicked the catecholamines, except that they were not blocked by propranolol. The slow responses were blocked by: (a) Ca²⁺-free solution, (b) 1 mm Mn²⁺, and (c) verapamil (0.05 μg/ml), suggesting that an inward Ca²⁺ current plays a key role in the response. In hearts perfused with normal Ringer, these conditions greatly depressed the contractions at a time when there was little or no effect on the shape and duration of the action potentials. Sr²⁺ and Ba²⁺ could replace Ca²⁺ in maintaining the response. Na⁺ is also required for the responses, because the magnitude, duration, and rate of rise of the response diminished in lowered [Na⁺]_o; the responses disappeared in 0 to 30 mm Na⁺. Ouabain (10^?5m) suppressed the CA- or MX-induced response. Continuous perfusion with dc-AMP or ATP (10^?4m) slowly induced the slow responses even in the presence of propranolol. The Ca²⁺ ionophore, X-537A, also induced the slow responses, but its effect was blocked by propranolol, suggesting that its action was mediated by endogenous CA release. Metabolic poisons, hypoxia, or ischemia blocked the slow responses. The following conclusions were drawn from the results: (a) the induced slow response is dependent on both Ca²⁺ and Na⁺ ions; (b) the underlying mechanism requires both Na⁺ and Ca²⁺ for its operation; (c) c-AMP is implicated in the control of the activities of this mechanism; (d) the production and/or maintenance of the mechanism is energy dependent; and (e) inactivation of the slow response mechanism results in electromechanical uncoupling.     

Methylxanthine discrimination in the rat: possible benzodiazepine and adenosine mechanisms

Rats were trained to discriminate either caffeine or theophylline from saline using a two-lever discrimination paradigm. Since methylxanthines have been found to interfere with agonist binding at both adenosine and benzodiazepine (BDZ) receptors, chlordiazepoxide (CDP) and L-PIA (an adenosine analog) were tested for generalization to and blockade of both xanthine cues. Neither L-PIA nor CDP generalized to either xanthine cue, although both produced dose-related decreases in response rate. CDP, but not L-PIA, produced dose-related decreases in drug-lever responses when combined with training doses of caffeine or theophylline. Response rates indicated a complex interaction between the xanthines and both L-PIA and CDP. When combined with the caffeine training dose, pentobarbital also produced a dose-dependent decrease in response rate but not in drug lever choices. Finally, papaverine generalized to the caffeine cue in a dose-dependent fashion. In a second experiment, rats trained to discriminate CDP from saline showed no generalization in L-PIA tests. CDP-appropriate responding was not significantly affected when the CDP training dose was combined with caffeine. These data indicate that: (a) methylxanthine interactions with L-PIA and CDP on response rate likely involve blockade of adenosine mechanisms; (b) the xanthine cue does not appear to depend on interactions with adenosine receptors; and (c) the xanthine cue may involve effects on cyclic AMP activity and/or interaction with the BDZ/GABA receptor complex.     

Pentoxifylline induces the shedding of L-selectin on polymorphonuclear cells by stimulation via adenosine receptor as well as by the inhibition of phosphodiesterase

We investigated the effects of pentoxifylline (PTX) on the expression of L-selectin on polymorphonuclear leukocytes (PMN). PTX induced the down-regulation of L-selectin expression in dose- and time-dependent manner. The measurement of soluble L-selectin in the culture medium by ELISA indicated that the down-regulation of L-selectin expression by PTX was due to the shedding of L-selectin from PMN. The mechanism by which PTX induced the shedding of L-selectin was investigated. The concentration of intracellular cyclic AMP (cAMP) was increased after treatment of PMN with PTX. However, an elevation of cAMP induced by dibutyryl cAMP (dbcAMP) as well as other methylxanthine derivatives (caffeine, aminophylline, and theophylline) did not induce the shedding of L-selectin. Although stimulation of the adenosine receptor with 5′-N-ethylcarboxamidoadenosine (NECA) or 5′-(N-cyclopropyl)-carboxamido-adenosine (CPCA) adenosine receptor agonists did not induce the shedding of L-selectin, shedding of L-selectin was demonstrated when PMN was incubated simultaneously with rolipram, a phosphodiesterase (PDE) inhibitor, and CPCA. Moreover, shedding of L-selectin induced by PTX was attenuated by aminophylline, an adenosine receptor antagonist. These results indicated that PTX induces the shedding of L-selectin on PMN by stimulation via the adenosine receptor as well as inhibition of PDE. Received: August 1, 2000 / Accepted: September 19, 2000     

Differential contributions of theobromine and caffeine on mood, psychomotor performance and blood pressure

The combination of theobromine and caffeine, methylxanthines found in chocolate, has previously been shown to improve mood and cognition. However, it is unknown whether these molecules act synergistically. This study tested the hypothesis that a combination of caffeine and theobromine has synergistic effects on cognition, mood and blood pressure in 24 healthy female subjects. The effects of theobromine (700 mg), caffeine (120 mg) or the combination of both, or placebo were tested on mood (the Bond-Lader visual analog scale), psychomotor performance (the Digit Symbol Substitution Test (DSST)) and blood pressure before and at 1, 2 and 3 h after administration. Theobromine alone decreased self-reported calmness 3 h after ingestion and lowered blood pressure relative to placebo 1 h after ingestion. Caffeine increased self-reported alertness 1, 2 and 3 h after ingestion and contentedness 1 and 2 h after ingestion, and increased blood pressure relative to placebo (at 1 h). The combination of caffeine + theobromine had similar effects as caffeine alone on mood, but with no effect on blood pressure. There was no treatment effect on DSST performance. Together these results suggest that theobromine and caffeine could have differential effects on mood and blood pressure. It was tentatively concluded that caffeine may have more CNS-mediated effects on alertness, while theobromine may be acting primarily via peripheral physiological changes.     

Interaction of carbamazepine and other drugs with adenosine (A1 and A2) receptors

The tricyclic anticonvulsant carbamazepine (CBZ) is effective in pain and affective disorder, but the mechanism of action for this drug has not been defined. Recently it was reported that CBZ had interaction with adenosine receptor, which is related to the inhibition of release of neurotransmitter.In the present study, we investigated the in vitro effects of CBZ and other drugs upon adenosine receptor binding using ³H-l-phenylisopropyladenosine (A₁) and ³H-N-ethylcarboxamidoadenosine (A₂). The following results were obtained: 1) CBZ and its derivative oxcarbazepine inhibit ³H-PIA binding at therapeutic plasma level (20–30 M) more than they inhibit ³H-NECA binding; 2) Theophylline and caffeine, methylxanthines, which are adenosine antagonists, inhibit both bindings; 3) Other anticonvulsants such as phenobarbital, phenytoin and valproate and still other psychotropic drugs such as diazepam, imipramine and chlorpromazine have little or no effect on both bindings.These findings suggest that anticonvulsive and sedative effects of CBZ and its derivatives appear due to action on adenosine receptors (A₁ and partially A₂) at the therapeutic level and methylxanthines have stimulant and convulsant effects due to occupation on both A₁ and A₂ adenosine receptors.     

Pharmacokinetics,pharmacodynamics and metabolism of caffeine in newborns

The plasma elimination half-life of caffeine in the newborn is approximately 100 h. Caffeine is rapidly absorbed with complete bioavailability following oral dosing. Switching between parenteral and oral administration requires no dose adjustments. Caffeine has wide interindividual pharmacodynamic variability and a wide therapeutic index in preterm newborns. Thresholds of measurable efficacy on respiratory drive have been documented at plasma levels around 2 mg/L. At these low levels, caffeine competitively inhibits adenosine receptors (A1 and A2A). The toxicity threshold is ill-defined and possibly as high as 60 mg/L which can be lethal in adults. High doses of caffeine may produce better control of apnea. However, at high systemic drug concentrations, the pharmacodynamic actions of caffeine become more complex and worrisome. They include inhibition of GABA receptors and cholinergic receptors in addition to adenosine receptor inhibition, intracellular calcium mobilization and actions on adrenergic, dopaminergic and phosphodiesterase systems. The role of pharmacogenomic factors as determinants of neonatal pharmacologic response and clinical effects remains to be explored.