Disease relevance of safrole

• Biology of hepatocellular neoplasia in the mouse. I. Histogenesis of safrole-induced hepatocellular carcinoma [1].
• After 36, 52, and 75 weeks of safrole treatment, hepatocellular adenomas were noted with altered enzyme histochemical profiles [2].
• The carcinogens thioacetamide, natulan, auramine, safrole, and 1'-hydroxysafrole increased mitotic recombination in S. cerevisiae D3 (the last compound was marginally positive), but they were negative in assays with Salmonella typhyimurium [3].
• Sequential alterations in enzyme histochemical profiles and reaction of hepatocytes to rapid iron overload were examined in male BALB/c mice during chronic, safrole exposure [2].
• 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 [4].

Psychiatry related information on safrole

• The possible consequences of these results for the effects of genetic polymorphisms and life style factors on the bioactivation of safrole are discussed [5].

High impact information on safrole

• At 24 weeks after initiation of safrole treatment, foci of enzyme-altered hepatocytes were noted [2].
• In both maternal and fetal tissues, safrole exhibited preferential binding to liver DNA [4].
• As safrole-DNA adducts have been detected in 77% (23/30) of the OSCC tissues from Taiwanese oral cancer patients with a BQ chewing history, we cannot rule out the possibility that safrole or other carcinogens present in the BQ may cause a similar pattern of mutagenesis [6].
• Determination of the role of safrole and other carcinogens present in BQ on the pattern of p53 gene mutation in OSCC will require further study [6].
• 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 [7].

Chemical compound and disease context of safrole

• Collectively, the data suggest that in human oral cancer cells, safrole induced a [Ca2+]i rise by causing release of stored Ca2+ from the endoplasmic reticulum in a phospholipase C- and protein kinase C-independent fashion and by inducing Ca2+ influx via nifedipine-sensitive Ca2+ entry [8].
• 8 carcinogens generally found to be non-mutagenic for Salmonella were tested: 2 showed DNA-damaging properties (mitomycin C, 1,2-dimethylhydrazine), 5 failed to do so (actinomycin D, griseofulvin, thioacetamide, diethylstilbestrol, safrole), and one (thiourea) was not toxic, so that no classification was possible [9].
• Numerous human and animal intoxications have been associated with naturally occurring components, including pyrrolizidine alkaloids, tannins, and safrole [10].
• The toxicity order for manganese in Sassafras sandy loam was E. crypticus>E. fetida>F. candida, with EC20 values of 116, 629, and 1209 mg kg(-1), respectively [11].

Biological context of safrole

• Altered fidelity of a nucleic acid modifying enzyme, T4 polynucleotide kinase, by safrole-induced DNA damage [12].
• 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 [7].
• We asked whether safrole and OAT induce GGT expression in preneoplastic foci or if these compounds select for a distinct set of lesions that can be identified by their GGT-positive phenotype [13].
• Previously, we found that safrole oxide could trigger vascular endothelial cell (VEC) apoptosis [14].
• 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] [15].

Anatomical context of safrole

• These findings indicate that the functional pineal gland plays an important role in oncostatic actions of carcinogens such as safrole [16].
• The 1'-hydroxylation of safrole was characterized in a variety of in vitro test systems, including Supersomes, expressing individual human P450 enzymes to a high level, and microsomes derived from cell lines expressing individual human P450 enzymes to a lower, average human liver level [5].
• Additionally, a correlation study was performed, in which safrole was incubated with a series of 15 human liver microsomes, and the 1'-hydroxylation rates obtained were correlated with the activities of these microsomes toward specific substrates for nine different isoenzymes [5].
• 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 [17].
• Collectively, the data suggest that in PC3 cells, safrole induced a [Ca2+]i increase by causing Ca2+ release from the endoplasmic reticulum in a phospholipase C- and protein kinase C-independent fashion, and by inducing Ca2+ influx [18].

Associations of safrole with other chemical compounds

• 2. Agents (3-methylcholanthrene, benzo[a]-pyrene, polychlorinated biphenyls, 2,3,7,8-tetrachlorodibenzo-p-dioxin and beta-naphthoflavone) that result in the induction of cytochrome P-448 caused a marked increase in two polypeptides of 54000 and 56000 mol.wt., whereas safrole and isosafrole induced only the former polypeptide [19].
• Thus, high nocturnal levels of melatonin were protective against safrole-induced DNA damage [16].
• Human cytochrome p450 enzyme specificity for bioactivation of safrole to the proximate carcinogen 1'-hydroxysafrole [5].
• These findings illustrate that melatonin preserves macromolecules including DNA, protein and lipid from oxidative damage following the administration of the chemical carcinogen, safrole, after exposure to ionizing radiation, following glutathione depletion, and after administration of the free radical generating herbicide, paraquat [20].
• Genotoxic effects of eugenol, isoeugenol and safrole in the wing spot test of Drosophila melanogaster [21].

Gene context of safrole

• Safrole strongly inhibited CYP1A2, CYP2A6, and CYP2E1 activities with IC(50) values less than 20 microM [22].
• These results revealed that safrole was a potent inhibitor of human CYP1A2, CYP2A6, and CYP2E1 [22].
• In the present study, the cytochrome P450 mediated bioactivation of safrole to its proximate carcinogenic metabolite, 1'-hydroxysafrole, has been investigated for the purpose of identifying the human P450 enzymes involved [5].
• Suppressing Akt phosphorylation and activating Fas by safrole oxide inhibited angiogenesis and induced vascular endothelial cell apoptosis in the presence of fibroblast growth factor-2 and serum [23].
• The results showed that safrole oxide inhibited angiogenesis and induced VEC apoptosis in the presence of FGF-2 and serum [23].

Analytical, diagnostic and therapeutic context of safrole

• Biology of hepatocellular neoplasia in the mouse. III. Electron microscopy of safrole-induced hepatocellular adenomas and hepatocellular carcinomas [24].
• 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) [25].
• Abuse of nutmeg (Myristica fragrans Houtt.): studies on the metabolism and the toxicologic detection of its ingredients elemicin, myristicin, and safrole in rat and human urine using gas chromatography/mass spectrometry [26].
• Determination of safrole, dihydrosafrole, and chloromethyldihydrosafrole in piperonyl butoxide by high-performance liquid chromatography [27].
• GC-MS and HPLC analyses of the essential oils of the leaves and stem revealed that safrol (25) was the major component of the oils [28].

References