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PubMed1979

The mutagenicities of safrole, estragole, eugenol, trans-anethole, and some of their known or possible metabolites for Salmonella typhimurium mutants.

Safrole, estragole, anethole, and eugenol and some of their known or possible metabolites were tested for mutagenic activity for S. typhimurium TA1535, TA100, and TA98. Highly purified 1'-hydroxyestragole and 1'-hydroxysafrole were mutagenic (approximately 15 and 10 revertants/micromole, respectively) for strain TA100 in the absence of fortified liver microsomes; trans-anethole and estragole appeared to have very weak activity. 3'-Hydroxyanethole was too toxic for an adequate test. Supplementation with NADPH-fortified rat-liver microsomes and cytosol converted 3'-hydroxyanethole to a mutagen(s) and increased the mutagenic activities for strain TA100 of 1'-hydroxyestragole, 1'-hydroxysafrole, estragole, and anethole. No mutagenicity was detected for safrole or eugenol with or without added NADPH-fortified liver preparations. The electrophilic 2',3'-oxides of safrole, 1'-hydroxysafrole, 1'-acetoxysafrole, 1'-oxosafrole, estragole, 1'-hydroxyestragole, and eugenol showed dose-dependent mutagenic activities for strain TA1535 in the absence of fortified liver microsomes. These mutagenic activities ranged from about 330 revertants/micromole for 1'-oxosafrole-2',3'-oxide to about 7000 revertants/micromole for safrole-2',3'-oxide. The arylalkenes, their hydroxylated derivatives, or their epoxides did not show mutagenic activity for strain TA98, except for 1'-oxosafrole-2',3'-oxide, which had weak activity. Since the arylalkenes are hydroxylated and/or epoxidized by hepatic microsomes, hydroxy and epoxide derivatives appear to be proximate and ultimate mutagenic metabolites, respectively, of the arylalkenes.

Anisoles↗
PubMed1977

Absorption, metabolism and excretion of safrole in the rat and man.

The metabolic disposition of different doses of [14C] safrole were studied in rat and man. In both species, small amounts of orally administered safrole were absorbed rapidly and then excreted almost entirely within 24 h in the urine. In the rat, when the dose was raised from 0.6 to 750 mg/kg, a marked decrease in the rate of elimination occurred as only 25% of the dose was excreted in the urine in 24 h. Furthermore, at the high dose level, plasma and tissue concentrations of both unchanged safrole and its metabolites remained elevated for 48 h probably indicating impairment of the degradation/excretion pathways. The main urinary metabolite in both species was 1,2-dihydroxy-4-allylbenzene which was excreted in a conjugated form. Small amounts of eugenol or its isomer 1-methoxy-2-hydroxy-4-allylbenzene were also detected in rat and man. 1'-Hydroxysafrole, a proximate carcinogen of safrole, and 3'-hydroxyisosafrole were detected as conjugates in the urine of the rat. However, in these investigations we were unable to demonstrate the presence of the latter metabolites in man.

Adult↗
PubMed2005

A traditional method of Cinnamomum carolinense preparation eliminates safrole from a therapeutic Pohnpean tea.

Cinnamomum carolinense, locally known as madeu, is a tree endemic to the volcanic mountains of the Island of Pohnpei in the Eastern Carolines of the South Pacific. The bark is harvested from trees and brewed to make a medicinal tea and hot beverage that is regularly consumed. Many species of Cinnamomum contain the known hepatocarcinogen safrole, sparking concern regarding habitual consumption of this beverage. HPLC-PDA analysis confirmed the presence of the carcinogen in alcoholic extracts of Cinnamomum carolinense bark shavings (0.435%, w/w), but safrole was not detected in the tea. The limit of detection and limit of quantitation of safrole were determined to be 1.25 and 3.75 microg/mL, respectively. The traditional preparation method, which boils the bark shavings, degrades the safrole.

Beverages↗
PubMed2005

Genotoxic effects of eugenol, isoeugenol and safrole in the wing spot test of Drosophila melanogaster.

In the present study, the phenolic compounds eugenol, isoeugenol and safrole were investigated for genotoxicity in the wing spot test of Drosophila melanogaster. The Drosophila wing somatic mutation and recombination test (SMART) provides a rapid means to evaluate agents able to induce gene mutations and chromosome aberrations, as well as rearrangements related to mitotic recombination. We applied the SMART in its standard version with normal bioactivation and in its variant with increased cytochrome P450-dependent biotransformation capacity. Eugenol and safrole produced a positive recombinagenic response only in the improved assay, which was related to a high CYP450-dependent activation capacity. This suggests, as previously reported, the involvement of this family of enzymes in the activation of eugenol and safrole rather than in its detoxification. On the contrary, isoeugenol was clearly non-genotoxic at the same millimolar concentrations as used for eugenol in both the crosses. The responsiveness of SMART assays to recombinagenic compounds, as well as the reactive metabolites from eugenol and safrole were considered responsible for the genotoxicity observed.

Animals↗
PubMedDate not supplied

Evidence that 4-allyl-o-quinones spontaneously rearrange to their more electrophilic quinone methides: potential bioactivation mechanism for the hepatocarcinogen safrole.

Several naturally occurring aromatic ethers, of which safrole [1-allyl-3,4-(methylenedioxy)-benzene] is one example, are hepatocarcinogens. One bioactivation pathway previously proposed for safrole involves hydroxylation of the benzyl carbon, conjugation with sulfate, and then alkylation of DNA with displacement of the sulfate group [Miller, J.A., and Miller, E.C. (1983) Br. J. Cancer 48, 1-15]. The fact that safrole is O-dealkylated to the corresponding catechol (hydroxychavicol, 1-allyl-3,4-dihydroxybenzene) indicates that quinoid formation is also possible and may contribute to the genotoxic and/or cytotoxic activity of this compound. In the present investigation we selectively oxidized hydroxychavicol to the corresponding o-quinone (HC-quinone, 4-allyl-3,5-cyclohexadiene-1,2-dione) or p-quinone methide (HC-QM, 2-hydroxy-4-allylidene-2,5-cyclohexadien-1-one) and trapped these reactive electrophiles with glutathione (GSH). The GSH adducts were fully characterized by UV, NMR, and mass spectrometry. Microsomal incubations with safrole or hydroxychavicol in the presence of glutathione produced only o-quinone glutathione conjugates. However, if the trapping agent (GSH) was added after an initial incubation of 10 min, both o-quinone and p-quinone methide GSH conjugates were observed. The first-order rate constant of isomerization was estimated from the decrease in HC-quinone GSH adducts to be 1.9 x 10(-3) s-1 (t1/2 = 9 min). Kinetic studies showed that while HC-QM reacts rapidly with water, the model o-quinone (4-tert-butyl-3,5-cyclohexadiene-1,2-dione), which cannot isomerize to a quinone methide, was remarkably resistant to hydrolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

In vivo genotoxicity and DNA adduct levels in the liver of rats treated with safrole.

The induction of chromosome aberrations, sister chromatid exchanges (SCEs), and the formation of DNA adducts was studied in hepatocytes of F344 rats exposed in vivo to safrole. Hepatocytes were isolated 24 h after a single dose of safrole or five repeated doses (once a day) by gastric intubation and allowed to proliferate in Williams' medium E supplemented with epidermal growth factor. Cells were fixed after 48 h in culture. Safrole-DNA adducts were detected by a nuclease P1-enhanced 32P-post-labeling assay in isolated hepatocytes from the rats. While a single dose was not sufficient to induce detectable levels of chromosome aberrations at the time of assay, five repeated doses induced these changes with a maximum frequency of 13.4%, compared with the control value of 1.8%. Both a single dose and five repeated doses induced significant SCEs, to a maximum frequency of 0.81 SCEs per chromosome, while the control value was 0.59 SCEs per chromosome. Two major and two minor DNA adducts were detected after treatment with either a single dose or five repeated doses. The maximum amount of total DNA adducts was 89.8 DNA adducts/10(7) nucleotides. These results show that safrole is a genotoxic carcinogen in the rat liver in vivo and suggest that the cytogenetic effects of this compound may result from covalent DNA modification in the rat liver. This in vivo cytogenetic assay should provide a useful means of evaluation of the genotoxicity of hepatocarcinogens.

Animals↗
PubMed1984

32P-post-labelling analysis of DNA adducts formed in the livers of animals treated with safrole, estragole and other naturally-occurring alkenylbenzenes. I. Adult female CD-1 mice.

The binding of a series of alkenylbenzenes to liver DNA of adult female CD-1 mice, isolated 24 h after i.p. administration of non-radioactive test compound (2 or 10 mg/mouse), was investigated by a modified 32P-post-labelling assay. The known hepatocarcinogens, safrole, estragole and methyleugenol, exhibited the strongest binding to mouse-liver DNA (1 adduct in 10 000 - 15 000 DNA nucleotides or 200 - 300 pmol adduct/mg DNA after administration of a 10 mg dose), while several related compounds, which have not been shown thus far to be carcinogenic in rodent bioassays, bound to mouse-liver DNA at 3 - 200x lower levels. The latter compounds included allylbenzene, anethole, myristicin, parsley apiol, dill apiol and elemicin. Eugenol did not bind. Low binding to mouse-liver DNA was also observed for the weak hepatocarcinogen, isosafrole. Two main 32P-labelled adducts, which appeared to be guanine derivatives, were detected for each of the binding chemicals on thin-layer chromatograms. The loss of safrole adducts from liver DNA was biphasic: a rapid loss during the first week (t 1/2 approximately 3 days) was followed by a much slower decline up to 20 weeks after treatment (t 1/2 approximately 2.5 months). Adducts formed by reaction of 1'-acetoxysafrole, a model ultimate carcinogen, with mouse-liver DNA in vitro were chromatographically identical to safrole-DNA adducts formed in vivo. Pretreatment with pentachlorophenol, a known inhibitor of sulphotransferases, inhibited the binding of safrole to mouse-liver DNA, providing further evidence that the metabolic activation of the allylbenzenes proceeds by the formation of 1'-hydroxy derivatives as proximate carcinogens and 1'-sulphoöxy derivatives as ultimate carcinogens.

Allylbenzene Derivatives↗
PubMed1980

Ligand binding of safrole to cytochrome P-450.

Safrole, a hepatocarcinogen, is converted by the microsomal mono-oxygenase system to a reactive intermediate which interacts with cytochrome P-450 to form a ligand complex. The formation of this complex is accompanied by loss of mono-oxygenase activity. The present study describes the interaction of the safrole reactive intermediate with microsomes from phenobarbital, 3-methylcholanthrene and safrole pretreated animals.

Animals↗
PubMed1989

Safrole, eugenol and methyleugenol induce intrachromosomal recombination in yeast.

Deletion of an integrated plasmid, a specific type of intrachromosomal recombination, was evaluated for inducibility with the phenylpropenes safrole, eugenol and methyleugenol in the yeast Saccharomyces cerevisiae. These phenylpropenes are found in food products, spices, pharmaceuticals and clove cigarettes. Safrole and eugenol are known carcinogens in animals and methyleugenol is a suspected carcinogen. These phenylpropenes are not detectable by the Ames assay and most other short-term tests used currently in predictive carcinogenesis. Like safrole, which has been shown to be nonmutagenic with the Ames assay, eugenol and methyleugenol were found to be nonmutagenic with the Ames assay. In contrast, with the yeast assays which screen for intra- and inter-chromosomal recombination in logarithmic phase cultures, all 3 compounds gave a positive dose-related response. These results demonstrate further that the yeast system can be modified easily to detect various genetic endpoints and that it deserves serious consideration as a test system for predictive carcinogenesis.

Adenine↗
PubMed1990

A comparison of DNA adduct formation in white blood cells and internal organs of mice exposed to benzo[a]pyrene, dibenzo[c,g]carbazole, safrole and cigarette smoke condensate.

Measurement of tissue/cell DNA adducts represents a suitable monitor of carcinogen exposure because the majority of chemical mutagens/carcinogens react with DNA, forming covalent adducts, a key event in the initiation of chemical carcinogenesis. Investigations of DNA-adduct formation in vivo in white blood cells (WBC) versus target tissues, i.e. internal organs for most carcinogens, is expected to yield useful information about the suitability of WBC for biomonitoring and risk assessment. For this purpose, female ICR mice were given 0.4 mmole/kg benzo[a]pyrene (BP), 0.045 mmole/kg dibenzo[c,g]carbazole (DBC) or 2.47 mmole/kg safrole by oral gavage or 4 daily doses (equivalent to 3 cigarettes) of cigarette-smoke condensate (CSC) by topical application. At 24 h after dosing, DNA adducts were detected by a nuclease P1-enhanced 32P-postlabeling assay [M.V. Reddy and K. Randerath, Carcinogenesis, 7 (1986) 1543] in WBC and internal tissues treated with individual carcinogens, while CSC treatment elicited aromatic adducts in most tissues but not in WBC. Adduct patterns of WBC DNA were qualitatively similar to those of internal organs, but adduct amounts varied. BP, a systemic carcinogen, bound nearly as much to WBC DNA as to target-tissue DNA samples; whereas the liver carcinogens, DBC and safrole, bound to WBC DNA considerably less (22- and 51-fold, respectively) compared with liver DNA. The number of adducts in 10(7) nucleotides of WBC, liver, lung, kidney and spleen DNA, respectively, were: 2, 5, 3, 2 and 3 with BP; 6, 131, 6, 14 and 4 with DBC; 5, 238, 3, 5 and 0.6 with safrole. For CSC, these values were 0, 1 and 0.02 in WBC, lung and spleen, respectively. Our results show that carcinogen binding to WBC DNA does not reflect binding to target-tissue DNA in a quantitative sense for the carcinogens studied except for BP, and that WBC are not suitable surrogates for monitoring CSC exposure by DNA-adduct measurement after topical application. The CSC data in mice was consistent with the previous findings in humans that smokers' tissues but not WBC show smoking-related bulky/aromatic DNA adducts, as measured by 32P-postlabeling.

Animals↗
PubMed2005

Safrole oxide induces apoptosis by activating caspase-3, -8, and -9 in A549 human lung cancer cells.

Previously we found that 3,4-(methylenedioxy)-1-(2',3'-epoxypropyl)-benzene (safrole oxide) induced a typical apoptosis in A549 human lung cancer cells. In this study, we further investigated which caspases were activated by safrole oxide during the apoptosis. The data showed that the activity of caspase-3, -8, and -9 was significantly enhanced by the compound, which suggested that safrole oxide might be used as a caspase promoter to initiate lung cancer cell apoptosis.

Antineoplastic Agents↗
PubMed2003

Augmented mRNA expression of tissue inhibitor of metalloproteinase-1 in buccal mucosal fibroblasts by arecoline and safrole as a possible pathogenesis for oral submucous fibrosis.

Oral submucous fibrosis (OSF) is an oral precancerous condition, and is associated with betel quid (BQ) chewing habits. It is a disorder of excessive deposition of collagen in the connective tissues that results from disruption in the regulation of the equilibrium between matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs). Elevated TIMP-1 protein has been thought to be associated with oral fibrosis, however whether TIMP-1 expression in OSF is modulated at the transcriptional level is still unknown. The present study used arecoline, arecaidine and safrole, which are thought to be major toxic ingredients in BQ, as candidates to explore the role of TIMP-1 expression in OSF pathogenesis. Fresh tissue biopsies of oral mucosa from 20 OSF males were included in this study, and fibroblasts were cultured from one OSF buccal mucosa and one normal buccal mucosa of the same OSF patient. To quantify the TIMP-1 expression, enzyme-linked immunosorbent assay (ELISA) was used in the present study. The results indicated that OSF fibroblasts produced more TIMP-1 protein (569.2+/-79.5 ng/ml) than normal fibroblasts (303.0+/-59.3 ng/ml) from the same patients, and the mRNA expression of TIMP-1 in OSF fibroblasts was higher (1.76 fold) than normal fibroblasts of the same patients. Arecoline and safrole significantly elevated TIMP-1 protein and mRNA expression. We concluded that increased mRNA expression of TIMP-1 in buccal mucosal fibroblasts by arecoline and safrole is a possible pathogenesis for oral submucous fibrosis.

Adult↗
PubMed2004

Identification of the main human cytochrome P450 enzymes involved in safrole 1'-hydroxylation.

Safrole is a natural plant constituent, found in sassafras oil and certain other essential oils. The carcinogenicity of safrole is mediated through 1'-hydroxysafrole formation, followed by sulfonation to an unstable sulfate that reacts to form DNA adducts. To identify the main cytochrome P450 (P450) involved in human hepatic safrole 1'-hydroxylation (SOH), we determined the SOH activities of human liver microsomes and Escherichia coli membranes expressing bicistronic human P450s. Human liver (n = 18) microsomal SOH activities were in the range of 3.5-16.9 nmol/min/mg protein with a mean value of 8.7 +/- 0.7 nmol/min/mg protein. In human liver (n = 3) microsomes, the mean K(m) and V(max) values of SOH were 5.7 +/- 1.2 mM and 0.14 +/- 0.03 micromol/min/nmol P450, respectively. The mean intrinsic clearance (V(max)/K(m)) was 25.3 +/- 2.3 microL/min/nmol P450. SOH was sensitive to the inhibition by a CYP2C9 inhibitor, sulfaphenazole, and CYP2E1 inhibitors, 4-methylpyrazole and diethyldithiocarbamate. The liver microsomal SOH activity showed significant correlations with tolbutamide hydroxylation (r = 0.569) and chlorzoxazone hydroxylation (r = 0.770) activities, which were the model reactions catalyzed by CYP2C9 and CYP2E1, respectively. Human CYP2C9 and CYP2E1 showed SOH activities at least 2-fold higher than the other P450s. CYP2E1 showed an intrinsic clearance 3-fold greater than CYP2C9. These results demonstrated that CYP2C9 and CYP2E1 were the main P450s involved in human hepatic SOH.

Cytochrome P-450 Enzyme Inhibitors↗
PubMed1993

Altered fidelity of a nucleic acid modifying enzyme, T4 polynucleotide kinase, by safrole-induced DNA damage.

Mouse liver DNA adducted with metabolites of the spice constituent safrole (1-allyl-3,4-methylenedioxybenzene), when analyzed via the bisphosphate version of the 32P-postlabeling assay, exhibits two major adducts, which had been previously identified as N2-(trans-isosafrol-3'-yl)2'-deoxyguanosine 3',5'-bisphosphate (adduct 1) and N2-(safrol-1'-yl)2'-deoxyguanosine 3',5'-bisphosphate (adduct 2). However, analysis of the same DNA preparation by the dinucleotide/monophosphate version of the assay gave two additional spots on PEI-cellulose TLC whose nature was clarified in the present study. Several enzymes (T4 polynucleotide kinase, nuclease P1, venom phosphodiesterase and spleen phosphodiesterase) were utilized to hydrolyze these compounds, and the products co-chromatographed on PEI-cellulose thin layers with radiolabeled and non-radioactive nucleotides of known structure. The additional spots were found to be adducted dinucleotides carrying 32P-label at both the 5'- and 3'-hydroxyls. T4 polynucleotide kinase-catalyzed 3'-phosphorylation was highly specific in that only dinucleoside monophosphate derivatives of adduct 1, with an unmodified purine in the 3'-position, were susceptible to both 5'- and 3'-phosphorylation by the enzyme. Thus, the structures of the two additional 32P-labeled safrole derivatives were pX1pAp and pX1pGp where X1 denotes N2-(trans-isosafrol-3'-yl)2'-deoxyguanosine. The official name of T4 polynucleotide kinase, ATP:5'-dephosphopolynucleotide 5'-phosphotransferase (EC 2.7.1.78), denotes the specific action of this enzyme as a 5'-phosphokinase. Although the enzyme has 3'-phosphatase activity at acidic pH, no 3'-kinase reaction has been previously reported. Possible implications for chemical carcinogenesis of the finding that carcinogen-DNA adducts can specifically alter the fidelity of protein-nucleotide interactions are discussed.

Animals↗
PubMed1977

[Mutagenicity of the metabolites of the epoxide-diol pathway of safrole and its analogs. Study on Salmonella typhimurium].

Mutagenicity of the metabolites of the expoxide-diol pathway of safrole and analogues was studied on Ames' strains with Ames' method. Safrole, eugenol, eugenolmethylether, estragol, allylbenzene and 1'-hydroxysafrole, are not mutagen on TA 1535, TA 100 (point mutation) and TA 1537, TA 1538, TA 98 (frameshift mutations) without activation system. The corresponding epoxides that we have synthetized, are mutagens and inducers of point mutation in TA 1535 and TA 100. Dose-effect curves show differences between the mutagen efficiencies of these epoxides probably in relation with their electrophilic properties. On the other hand the 2', 3'-dihydro-2',3'-dihydroxisafrole was not mutagen in Ames' test. These results confirm the promutagen character of safrole and analogues and the role of the epoxides as proximate carcinogens.

Carcinogens↗
PubMed1986

32P-postlabeling assay in mice of transplacental DNA damage induced by the environmental carcinogens safrole, 4-aminobiphenyl, and benzo(a)pyrene.

Transplacental exposure of fetuses to carcinogens is known to induce tumors in the offspring, often with a high incidence and short latency. While covalent adduction of DNA appears to be essential for tumor initiation, little is known about the binding of carcinogens to the DNA of fetal tissues. A sensitive 32P-postlabeling method enabled us to study the binding of the environmental carcinogens safrole (600 mumol/kg p.o.), 4-aminobiphenyl (800 mumol/kg), and benzo(a)pyrene (200 mumol/kg) to the DNA of various maternal and fetal tissues after administration of test carcinogens to pregnant ICR mice on day 18 of gestation. The results show that these carcinogens bound to the DNA of maternal and fetal liver, lung, kidney, heart, brain, intestine, skin, maternal uterus, and placenta, with organ-specific quantitative and qualitative differences. It was possible for the first time to analyze DNA adduct patterns in minute amounts of tissue, for example those available from fetal heart. The covalent binding index (mumol adducted nucleotides per mol of DNA nucleotides/mumol carcinogen administered per g body weight) 24 h after safrole treatment was estimated for the different organs and ranged from 0.1 to 247 and 0.1 to 5.8 for maternal and fetal DNA, respectively. Covalent binding index values of 0.2 to 13 and 0.1 to 0.3 for maternal and fetal DNA, respectively, were found for 4-aminobiphenyl. Benzo(a)pyrene treatment yielded covalent binding index values of 0.6 to 6.5 and 0.3 to 0.7 for maternal and fetal DNA, respectively. In both maternal and fetal tissues, safrole exhibited preferential binding to liver DNA. 4-Aminobiphenyl bound preferentially to DNA of maternal liver and kidney but showed no preference among fetal tissues. Benzo(a)pyrene exhibited weak tissue preference in both maternal and fetal organs. For all of the compounds studied, the fetal adduct levels were generally lower than the corresponding maternal adduct levels, especially when the level of maternal adduction was high. The major finding was that several carcinogens of diverse structure or their metabolites readily crossed the placenta and gave rise to DNA adducts in fetal organs. The resulting DNA damage in rapidly proliferating tissues may play a critical role in transplacental carcinogenesis.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1981

Biology of hepatocellular neoplasia in the mouse. I. Histogenesis of safrole-induced hepatocellular carcinoma.

A sequential, histologic analysis of the livers of male BALB/c mice chronically fed the hepatocarcinogen safrole (4,000 ppm) was performed at 2, 4, 8, 16, 24, 36, 52, and 75 weeks. The transplantability of selected lesions to syngeneic hosts was also assessed. Histopathologic liver alterations at 2, 4, 8, and 16 weeks induced hypertrophy of centrolobular hepatocytes, oval cell proliferation, fatty change in periportal hepatocytes, including basophilic, acidophilic, and clear cell, were noted. At 36 and 52 weeks, hepatocellular adenomas occurred in 4 of 10 and 7 of 10 mice, respectively. At 75 weeks they occurred in 5 of 5 mice. Adenomas were larger than a lobule in diameter compressed the adjacent parenchyma, and distorted the hepatic architecture. Individual adenomas were composed of a mixture of basophilic, acidophilic, clear, and lipid-laden cells, arranged in disorganized cords, one to three cells in thickness. None of the 10 adenomas tested grew upon subcutaneous transplantation into syngeneic hosts. Hepatocellular carcinomas (HPC) developed in 2 of 10 safrole-exposed mice at 52 weeks and 3 of 5 mice at 75 weeks. These lesions were large, multilobed and, unlike adenomas, seemed to invade adjacent parenchyma. The HPC were heterogeneous in cell composition. Their architecture was disorganized with trabeculae of 1-10 or more cells in thickness. No central veins or portal tracts were seen. All HPC proliferated when transplanted into syngeneic hosts. The results of this study demonstrated a sequential development of altered hepatocyte populations leading to HPC in safrole-treated mice. The transplantability of HPC indicated their malignant nature.

Adenoma↗
PubMed1982

Genotoxicity of safrole-related chemicals in microbial test systems.

The genotoxicity of safrole, 9 compounds that are structurally similar to safrole (anethole, cinnamaldehyde, cinnamyl alcohol, estragole, methyl eugenol, eugenol, isoeugenol, isosafrole, piperonal), 5 essential oils, cassia oil, cinnamon bark oil, clove oil, fennel oil) which contain the chemicals tested, and 1 oleoresin was studies in 3 microbial test systems. Only anethole showed mutagenicity in the Ames Salmonella reversion assay. All chemicals except anethole, estragole and isosafrole were positive in the Bacillus subtilis DNA-repair test (Rec assay) without S9. All samples tested were negative in the Escherichia coli WP2 uvrA reversion test. The essential oils and pimenta oleoresin were positive in the DNA-repair test. The results obtained are discussed in relation to the nature of the problems encountered with each test method.

1-Propanol↗