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PubMed2000

Hippuric acid as a major excretion product associated with black tea consumption.

1. Nine habitual tea-drinking volunteers were recruited and asked to follow a low-polyphenol and low-caffeine diet for 6 days and to provide daily 24-h urine samples. On day 4 of the experiment strong black tea brewed under standardized conditions was re-introduced to the volunteers' diet. 2. 1H-NMR and HPLC profiling of the urine samples indicated that consumption of black tea (6-10 mugs per day) was associated with a significant (p = 0.00017) increase in hippuric acid excretion relative to control, increasing from 153-512 to 742-1374 mg day(-1). The excretion of substantial amounts of hippuric acid has not previously been associated with black tea consumption. 3. For some volunteers, the quantity of benzoic acid processed exceeded the acceptable daily intake (ADI), but this is not considered to constitute any hazard. 4. A mass-balance analysis indicated that the necessary quantity of benzoic acid could not be obtained from the contents of gallic acid, flavanols, flavonol glycosides and theaflavins in black tea even if 100% transformation was obtained, suggesting that the thearubigins (the major and chemically ill-defined polyphenols of black tea) may be an important source.

Adult↗
PubMed1995

Inhibition of oncogene expression by green tea and (-)-epigallocatechin gallate in mice.

The effects of tea drinking on the tobacco-specific nitrosamine 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK)-induced mouse lung oncogene expression and the effect of topical application of the tea polyphenol component (-)-epigallocatechin-3-gallate (EGCG) on 12-O-tedradecanoylphorbol-13-acetate (TPA)-induced mouse skin oncogene expression were investigated. In the first experiment, mice were treated with NNK (1.3 mg/kg body wt ip) once a day for three days and were given 2% tea in drinking water during the whole experimental period. After four or eight weeks, the lung tissue of the mice treated with NNK displayed a significantly high level of expression in c-myc, c-raf, and c-H-ras oncogenes, and they were all inhibited by tea drinking with inhibitory rates of 50%, 20%, and 50%, respectively. In the second experiment, a single application of 10 nmol of TPA to mouse skin led to a marked increase in the transcripts' level of ornithine decarboxylase (ODC) gene, protein kinase C (PKC) gene, and c-myc oncogene at four hours after TPA administration. Topical application of EGCG (1 or 5 mumol) one hour before the application of TPA inhibited all TPA-induced gene expression in a dose-dependent fashion. These results confirm the anticarcinogenic effects of tea and suggest that a possible mechanism is the effect of tea on carcinogen-induced oncogene expression.

Animals↗
PubMed1998

Association of coffee, green tea, and caffeine intakes with serum concentrations of estradiol and sex hormone-binding globulin in premenopausal Japanese women.

Caffeine intake has been proposed to influence breast cancer risk. Its effect may be mediated by hormonal changes. The relationships between caffeine-containing beverages (coffee, green tea, black tea, oolong tea, and cola) and serum concentrations of estradiol and sex hormone-binding globulin were evaluated in 50 premenopausal Japanese women. Intakes of caffeine and caffeine-containing beverages were assessed by a semiquantitative food-frequency questionnaire. Blood samples were obtained from each woman on Days 11 and 22 of her menstrual cycle. High intakes of caffeinated coffee, green tea, and total caffeine were commonly correlated with increasing sex hormone-binding globulin on Days 11 and 22 of the cycle after controlling for potential confounders [Spearman correlation coefficients (r) ranged from 0.23 to 0.31]. Green tea but not caffeinated coffee intake was inversely correlated with estradiol on Day 11 of the cycle (r = -0.32, p = 0.04). Although the effect of caffeine cannot be distinguished from effects of coffee and green tea, consumption of caffeine-containing beverages appeared to favorably alter hormone levels associated with the risk of developing breast cancer.

Adult↗
PubMed2004

Green tea protection against age-dependent ethanol-induced oxidative stress.

Ethanol intoxication leads to oxidative stress, which may be additionally enhanced by aging. The aim of this study was to investigate the influence of green tea as a source of water-soluble antioxidants on the ability to prevent oxidative stress in aged rats sub-chronically intoxicated with ethanol. Two-, 12-, and 24-mo-old male Wistar rats were divided into 4 experimental groups: (1) control, (2) green tea, (3) ethanol, and (4) ethanol and green tea. Ethanol intoxication produced age-dependent decrease in the activity of serum superoxide dismutase, glutathione peroxidase, and reductase and in levels of glutathione (GSH), vitamins C, E, and A, and beta-carotene. Changes in the serum antioxidative ability were accompanied by enhanced oxidative modification of lipid (increase in lipid hydroperoxides, malondiadehyde, and 4-hydroxynonenal levels) and protein (rise in carbonyl group levels). Green tea partially protected against changes in antioxidant enzymatic as well as nonenzymatic parameters produced by ethanol and enhanced by aging. Administration of green tea significantly protects cellular components such as lipids and proteins against oxidative modification. Results indicate that green tea effectively protects blood serum against oxidative stress produced by ethanol as well as aging.

Aging↗
PubMed1997

Effect of tea flavonoid supplementation on the susceptibility of low-density lipoprotein to oxidative modification.

Dietary flavonoid intake has been reported to be inversely associated with the incidence of coronary artery disease. To clarify the possible role of tea flavonoids in the prevention of atherosclerosis, we investigated the effects of tea flavonoids on the susceptibility of low-density lipoprotein (LDL) to oxidative modification. In an in vitro study, catechins or theaflavins (25-400 mumol/L) were added to plasma and incubated for 3 h at 37 degrees C. Then, the LDL fraction was separated by ultracentrifugation. The oxidizability of LDL was estimated by measuring conjugated diene, thiobarbituric acid-reactive substances (TBARS), and lipid peroxides after cupric sulfate was added. TBARS and lipid peroxides in the supernates were also measured after incubation with macrophages. Catechins significantly (P < 0.01 by ANOVA) and dose-dependently prolonged the lag time before initiation of oxidation. Among the catechins, epigallocatechin gallate exerted the most marked effect, prolonging the oxidation lag time more than vitamin E at the same molar concentration. Theaflavins exerted stronger inhibitory effects than catechins. Macrophage-mediated LDL oxidation was also inhibited by adding these tea flavonoids to the plasma samples. In an in vivo study, 14 healthy volunteers consumed 750 mL black tea/d for 4 wk. After the subjects had consumed tea for 4 wk, the lag time before LDL oxidation was significantly (P < 0.01) prolonged from 54 to 62 min. This minor prolongation occurred despite much lower plasma flavonoids than were used in vitro. No significant change was observed in eight control volunteers. LDL exposed to tea flavonoids in vitro or in vivo reduced oxidizability. We speculate that tea flavonoids may have a role in ameliorating atherosclerosis.

Adult↗
PubMed1994

Selective induction of rat hepatic CYP1 and CYP4 proteins and of peroxisomal proliferation by green tea.

Rats were exposed to freshly prepared aqueous extracts of green tea (2.5% w/v) as the sole source of drinking water for 4 weeks. Hepatic cytochrome P450 activity was determined using chemical probes, showing selectivity for particular isoforms, and by immunoblot analysis employing polyclonal antibodies. Exposure to green tea gave rise to increases in the O-demethylation of methoxyresorufin and, to a lesser extent, in the dealkylations of ethoxyresorufin and pentoxyresorufin. An increase was also seen in lauric acid hydroxylation but, in contrast, the N-demethylation of erythromycin was inhibited. p-Nitrophenol oxidase activity was unaffected by the same treatment. Immunoblot analysis revealed increases in the apoprotein levels of CYP1A2 and CYP4A1 following treatment with green tea. A significant increase was also noted in the CN(-)-insensitive palmitoyl CoA oxidation and this was paralleled by an increase in the levels of the peroxisomal trifunctional protein determined immunologically. Hepatic S9 and microsomal preparations from tea-treated animals were more effective than controls in activating 2-amino-3-methylimidazol[4,5-f]quinoline and 2-aminoanthracene to mutagens in the Ames test. When N-nitrosopyrrolidine served as the promutagen, tea did not influence its mutagenicity when isolated microsomes comprised the activation system but a significant inhibition was observed when hepatic S9 was used. The above findings are discussed within the context of the established anticarcinogenic and anti-mutagenic properties of green tea.

Animals↗
PubMed1997

Inhibition of phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate-caused inflammatory responses in SENCAR mouse skin by black tea polyphenols.

Over the past 10 years many studies from several laboratories defined anticarcinogenic and anti-inflammatory effects of tea, a widely consumed beverage by the human population. Much of such work has been conducted with green tea or its polyphenolic constituents. Regarding black tea, studies have shown that its water extract affords protection against tumor promotion caused by chemical carcinogens or ultraviolet B radiation in murine skin carcinogenesis models. Several studies have shown that topical application of chemical tumor promoters to murine skin results in the induction of epidermal edema, hyperplasia and ornithine decarboxylase (ODC) and cyclo-oxygenase activities, and interleukin-1 alpha (IL-1alpha) and ODC mRNA expression. In this study, we assessed whether topical application of polyphenols isolated from black tea leaves (hereafter referred to as BTP) mainly consisting of theaflavine gallates and (-)-epigallocatechin-3-gallate, inhibits phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA)-caused induction of these markers of inflammatory responses in murine skin. Topical application of BTP (6 mg in 0.2 ml acetone/animal) 30 min prior to TPA application on to the mouse skin resulted in significant inhibition against TPA-caused induction of epidermal edema (40%, P < 0.01), hyperplasia (57%, P < 0.005), leukocytes infiltration (50%), and induction of epidermal ODC (57%) and pro-inflammatory cytokine IL-1alpha mRNA expression (69%). Pre-application of BTP to that of TPA also resulted in significant inhibition of TPA-caused induction of epidermal ODC (23-73%, P < 0.005-0.0001), and cyclo-oxygenase, in terms of prostaglandins metabolites formation (38-65%, P < 0.01-0.0005), enzyme activities. Our data indicate that the inhibition of TPA-caused changes in these markers of inflammatory responses in murine skin by BTP may be one of the possible mechanisms of chemopreventive effects associated with black tea against tumorigenesis. The results of this study suggest that black tea, specifically polyphenols present therein, may be useful against cutaneous inflammatory responses in human population.

Animals↗
PubMed2000

Prevention of the down-regulation of gap junctional intercellular communication by green tea in the liver of mice fed pentachlorophenol.

Much evidence has been documented supporting the hypothesis that the down-regulation of gap junctional intercellular communication (GJIC) is a cellular event underlying the tumor promotion process and that treatment to prevent the down-regulation or to up-regulate GJIC is important in preventing tumor promotion. We explored the potential preventive effects of green tea against the promoting action of pentachlorophenol (PCP) in mouse hepatocarcinogenesis, examining whether drinking green tea prevents the down-regulation of GJIC inhibition in the liver caused by tumorigenic doses of PCP. We used a modified in vivo GJIC assay, the incision loading/dye transfer method. Male B6C3F1 mice were given a green tea infusion for 1 week and then PCP was fed at a dose of 300 or 600 p.p.m. in the diet for the following 2 weeks, along with green tea treatment. A dose-related inhibition of GJIC in the hepatocytes was evident in the mice treated with PCP alone that was associated with a reduction in connexin32 (Cx32) plaques in the plasma membrane and an increase in the cell proliferation index. Drinking green tea significantly protected mice against GJIC inhibition, the reduction in Cx32 and the elevation of the labeling index. These findings suggest that green tea might act as an anti-promoter against PCP-induced mouse hepatocarcinogenesis via its ability to prevent down-regulation of GJIC.

Animals↗
PubMed2003

Tea and cancer prevention: studies in animals and humans.

The role of tea in protection against cancer has been supported by ample evidence from studies in cell culture and animal models. However, epidemiological studies have generated inconsistent results, some of which associated tea with reduced risk of cancer, whereas others found that tea lacks protective activity against certain human cancers. These results raise questions about the actual role of tea in human cancer that needs to be addressed. This article is intended to provide a better perspective on this controversy by summarizing the laboratory studies in animals and humans with emphasis on animal tumor bioassays on skin, lung, mammary glands and colon, and the molecular and cellular mechanisms affected by tea. Finally, a recent small pilot intervention study with green tea in smokers is presented.

Animals↗
PubMed2000

Tea consumption and risk of bladder and kidney cancers in a population-based case-control study.

Recent epidemiologic studies have suggested that tea may be protective against cancers of the urinary tract. The authors examined the association between usual adult tea consumption and risk of bladder and kidney cancers in a population-based case-control study that included 1,452 bladder cancer cases, 406 kidney cancer cases, and 2,434 controls. For bladder cancer, the age- and sex-adjusted odds ratios (OR) (95% confidence intervals (CI)) referent to nonusers of tea were 0.9 (0.7, 1.1) for <1.0 cup/day, 1.0 (0.8, 1.2) for 1.0-2.6 cups/day, and 0.9 (0.7, 1.1) for >2.6 cups/day (cutpoints for users based on the tertile distribution among controls). When more extreme cutpoints were used, persons who consumed >5 cups/day (>90th percentile) had a suggestive decreased risk (OR = 0.7; 95% CI 0.5, 1.0), but there was no evidence of a dose-response relation. In analyses stratified by median total beverage intake (2.6 liters/day), there was an inverse association with tea use among persons who consumed less than the median (OR = 0.5; 95% CI 0.3, 0.8) but no association for persons who consumed at or above the median. In contrast, for kidney cancer, there was no association with tea use. Adjustment for site-specific risk factors did not alter these results. This study offers only minimal support for an inverse association between tea consumption and bladder or kidney cancer risk.

Adult↗
PubMed2000

Tea and other beverage consumption and prostate cancer risk: a Canadian retrospective cohort study.

Using participants in the 1970-1972 Nutrition Canada Survey (NCS), a retrospective cohort study was conducted to assess the relationship between tea, as well as coffee, cola and alcohol, and the risk of developing prostate cancer. The mortality and cancer experience of male NCS participants aged 50-84 years was determined up to 31 December 1993. Among the 3400 survey participants included in the study, 145 developed prostate cancer. No association was observed between tea (predominantly black tea) intake and prostate cancer. Subjects who drank more than 500 ml of tea per day experienced virtually the same risk as those who reported no tea consumption (rate ratio (RR) 1.02, 95% confidence interval (CI) 0.62-1.65). Compared to those who reported no coffee drinking, men who averaged more than 250-ml per day experienced a 40% increase in risk (95% CI 0.84-2.32). Cola consumption was not associated with an increased risk of prostate cancer. Total alcohol consumption was not related to subsequent development of prostate cancer, although very moderate consumption of wine (< 10 g per day), relative to no consumption, showed an RR of 1.48 (95% CI 1.05-2.09). These data do not support an association between consumption of tea and prostate cancer risk.

Aged↗
PubMed2006

In vivo and in vitro effects of tea extracts on enterotoxigenic Escherichia coli-induced intestinal fluid loss in animal models.

OBJECTIVES: Enterotoxigenic Escherichia coli (ETEC) infection is a major cause of dehydrating diarrhoea in infants and early-weaned piglets living under subhygienic conditions. We studied the effect of different tea types and subfractions on the intestinal fluid and electrolyte losses involved in ETEC diarrhoea. MATERIALS AND METHODS: Jejunal segments of anaesthetised piglets were infected with ETEC or ETEC heat-labile toxin (LT) and subsequently perfused for 8 hours with control or tea solutions containing green or black tea extract (BTE) or 3 different BTE subfractions containing small-size, large-size or no phenolics. Changes in intestinal fluid and electrolyte net absorption were measured. To assess the antisecretory effects of tea, BTE was incubated before or after administration of the secretagogue forskolin in rat jejunal tissue placed in Ussing chambers and Cl- secretion measured as changes in short-circuit current (I(SC)). RESULTS: Enterotoxigenic E. coli infection of piglet jejunal segments significantly reduced net absorption of fluid, Na+ and Cl- and increased net secretion of K+ compared with controls. Perfusion of the ETEC-infected segments with both 3 g/L green tea extract and BTE significantly inhibited these disturbances in fluid and electrolyte balance. The BTE subfraction rich in polymeric phenolics but not the other subfractions improved the fluid and electrolyte balance. Addition of forskolin to rat jejunal tissue induced a significant increase in I(SC). Pretreating but not posttreating the jejunal tissue with BTE inhibited the forskolin-induced increase in I(SC). CONCLUSIONS: Tea may inhibit net fluid and electrolyte losses involved in secretory diarrhoea from ETEC.

Animals↗
PubMed1997

Inhibitory activity of green and black tea in a free radical-generating system using 2-amino-3-methylimidazo[4,5-f]quinoline as substrate.

Green tea and black tea inhibit colon carcinogenesis in rats exposed to the cooked meat mutagen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). In the present investigation, green tea, black tea and (-)-epigallocatechin gallate (EGCG) were shown to block the production of oxygen free radicals derived from IQ in the presence of NADPH-cytochrome P450 reductase. In kinetic studies using IQ as the substrate and DMPO as a free radical spin trap, EGCG increased the K(m) of the reaction without altering Vmax, suggesting competitive enzyme inhibition (Ki = 9.96 microM). This was confirmed in spectrophotometric studies using cytochrome c as the substrate, in which EGCG acted as a competitive inhibitor of NADPH-cytochrome P450 reductase (Ki = 9.7 microM). These results suggest that the inhibitory activities of green tea and black tea in electron spin resonance assays using IQ as the substrate for the reductase are related to an indirect effect on the enzyme rather than via direct scavenging of the free radicals. The possible implications of these findings are discussed in the context of pathways involved in the activation and detoxification of IQ in the colon.

Animals↗
PubMed2005

Levels of common antigens in determining pathogenicity of Curvularia eragrostidis in different tea varieties.

AIMS: Pathogenicity of Curvularia eragrostidis, a foliar fungal pathogen of tea was studied in 24 commercially cultivated tea varieties by analysing the antigenic patterns of host and pathogen with the help of immunoserological techniques. METHODS AND RESULTS: Initial testing by cut shoot inoculation technique followed by whole plant inoculation technique showed that among the varieties tested, TV12 was the most susceptible and TV25 most resistant. Antigen preparations from tea varieties, fungal pathogens (C. eragrostidis and Lasiodiplodia theobromae) and a nonpathogen (Gliocladium virens) were compared by immunodiffusion, immunoelectrophoresis and indirect ELISA to detect common antigens shared by host and pathogen. Common antigens were detected by immunodiffusion and immunoelectrophoresis only among susceptible varieties and the pathogens. Such antigens were not found between the pathogens and the resistant varieties and also between nonpathogens and tea varieties. However, ELISA revealed the presence of low level of common antigens between all combinations. A certain minimum level of antigens was present for compatible host-pathogen interaction. Indirect labelling of antibodies with fluorescein isothiocyanate (FITC) showed that cross-reactive antigens were found to be concentrated mainly in the epidermal cells and also spread throughout the cortical cells. CONCLUSION: Pathogenicity of C. eragrostidis to different varieties of tea was found to be related to the level of common antigens present between host and pathogen. SIGNIFICANCE AND THE IMPACT OF THE STUDY: Indirect ELISA proved to be valuable in screening commercially cultivated varieties of tea for their susceptibility to C. eragrostidis.

Animals↗
PubMed1998

Clinical trial on the effect of regular tea drinking on iron accumulation in genetic haemochromatosis.

BACKGROUND: Black tea is known to be a potent inhibitor of intestinal absorption of non-haem iron at least in healthy subjects. AIMS: To investigate this effect in patients with genetic haemochromatosis, and, more importantly, the effect of regular tea drinking on the accumulation of storage iron in these patients over one year. PATIENTS: Investigations were carried out on 18 patients with clinically proven genetic haemochromatosis. For the study of storage iron accumulation, they were separated into a group instructed to drink a particularly tannin rich tea regularly with meals and a control group. METHODS: Intestinal iron absorption from a test meal was measured using whole body counting. Body iron stores were evaluated quantitatively by exhaustive phlebotomy, using haemoglobin, saturation of serum iron binding capacity, and serum ferritin for the assessment of body iron status. RESULTS: A significant reduction in iron absorption was observed when the test meal was accompanied by drinks of tea instead of water. In the tea drinking group, the increase in storage iron was reduced by about one third compared with that of the control group. CONCLUSIONS: Regular tea drinking with meals reduces the frequency of phlebotomies required in the management of patients with haemochromatosis.

Adult↗
PubMed1984

Respiratory function in tea workers.

Respiratory function was studied in five groups of tea workers employed in processing different types of tea. The prevalence of almost all chronic respiratory symptoms was significantly higher in workers processing dog-rose, sage, and gruzyan tea than in control workers. During the Monday workshift there was a significant mean acute decrease in maximum expiratory flow rates at 50% vital capacity (range: 4.1-8.8%) and at 25% VC (range: 7.8-21.8%) except in those exposed to camomile. Acute reductions in forced expiratory volume in one second were considerably smaller and mostly not significant. Mean acute reductions on Wednesday were similar to those on Monday with no significant differences between preshift Monday and Wednesday data. Acute decreases in flow rates at low lung volumes suggest that the bronchoconstrictor effect of the dust acts mostly on smaller airways. Preshift administration of disodium cromoglycate significantly diminished acute reduction in flow rates except in workers processing Indian tea. A comparison of Monday preshift values of ventilatory capacity in tea workers with those in controls indicates that exposure to tea dust may, in some workers, lead to chronic respiratory impairment.

Adult↗
PubMedDate not supplied

A study of tea tree oil ototoxicity.

Tea tree oil shows promise as an effective treatment for a number of micro-organisms commonly associated with otitis externa and otitis media, but its possible ototoxicity has not been previously assessed. The ototoxicity of tea tree oil was examined in the guinea pig by measuring the thresholds of the compound auditory nerve action potential (CAP) to tone bursts before and after instillation of the oil into the middle ear. After 30 min of instillation, 100% tea tree oil caused a partial CAP threshold elevation at 20 kHz. A lower concentration of oil [2% tea tree oil dissolved in saline using 0.5% detergent (Tween-80)] did not cause any significant lasting threshold change after middle ear instillation for the same period of time. The latter concentration of oil is greater than the minimum inhibitory concentration reported for most micro-organisms in the effective spectrum of the oil and this suggests that this concentration may be safe and effective provided only short exposures (about 30 min) are used. The results suggest that high concentrations of tea tree oil applied to the round window for a relatively short time are to some extent ototoxic to the high-frequency region of the cochlea. Hence further study is needed to establish whether tea tree oil can be used with safety in the treatment of external and middle ear infections.

Animals↗
PubMed2004

Tea polyphenols inhibit acetyl-CoA:1-alkyl-sn-glycero-3-phosphocholine acetyltransferase (a key enzyme in platelet-activating factor biosynthesis) and platelet-activating factor-induced platelet aggregation.

BACKGROUND: Tea extracts have antiallergic and anti-inflammatory actions in rats and mice. However the mechanism through which tea polyphenols act in vivo are still incompletely understood. We found inhibitory effects of black tea extracts on an fMLP-induced aggregating response in a rabbit platelet-polymorphonuclear leukocyte (PMN) system. METHOD: To elucidate whether 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine (PAF) production in PMNs and/or PAF-stimulated platelet activation were inhibited, the effects of tea polyphenols were investigated on the enzyme activity of acetyl-CoA:1-alkyl-sn-glycero-3-phosphocholine acetyltransferase (EC 2.3.1.67), PAF biosynthesis in A23187-activated rabbit PMNs, and rabbit platelet aggregation. By comparing the inhibitory effects of 31 galloyl esters and gallic acid, the structure-inhibitory activity relationship was characterized. RESULTS: Theaflavin and its galloyl esters and pentagalloyl glucose were found to be potent inhibitors of the acetyltransferase (IC(50) = 28-58 microM) and the PAF biosynthesis as well as (-)-epicatechin-3-O-gallate (IC(50) = 72 +/- 13 microM) and (-)-epigallocatechin-3-O-gallate (IC(50) = 46 +/- 6 microM). On the other hand, flavan-3-ols without galloyl group at C-3 and gallic acid did not show significant enzyme inhibition. In addition, theaflavin and its galloyl esters (IC(50) = 32-77 microM) and geranyl gallate, farnesyl gallate and geranylgeranyl gallate (IC(50) = 6.4-7.6 microM) were found to be potent inhibitors of PAF- and TPA-induced rabbit platelet aggregation but not A23187-induced aggregation. CONCLUSIONS: Theaflavin and its galloyl esters in black tea extract, and isoprenyl gallates were potent inhibitors of PAF synthesis and platelet aggregation and these activities may be relevant to the claimed therapeutic effects of tea extracts.

Acetyltransferases↗