Cytotoxic Effects of Secosterols and Their Derivatives on Several Cultured Cells

Tomono, Susumu; Yasue, Yukari; Miyoshi, Noriyuki; Ohshima, Hiroshi

doi:10.1271/bbb.120758

Cited by 14 publications

(8 citation statements)

References 19 publications

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“…Human spleen lymphoblastoid TK6 cells were kindly gifted by Dr. Takeda Shunichi of Kyoto University and cultured in 5% HS/RPMI supplemented with 50 U/mL penicillin and 50 μg/mL streptomycin. Cytotoxicity of o -Ans and MxMxBD was determined using an aramarBlue assay as previously described. , Levels of phosphorylated histone H2A.X (γ-H2AX) were evaluated by flow cytometry using AlexaFluor 488 rabbit phospho-histone H2A.X (Ser139) antibody (Cell Signaling Technology, Beverly, MA).…”

Section: Methodsmentioning

confidence: 99%

o-Anisidine Dimer, 2-Methoxy-N⁴-(2-methoxyphenyl) Benzene-1,4-diamine, in Rat Urine Associated with Urinary bladder Carcinogenesis

Kobayashi

Toyoda

Tajima

et al. 2021

Chem. Res. Toxicol.

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Monocyclic aromatic amines, o-toluidine (o-Tol) and its structural analog o-anisidine (o-Ans), are IARC Group 1 and Group 2A urinary bladder carcinogens, respectively, and are involved in metabolic activation and DNA damage. Our recent study revealed that 2-methyl-N 4 -(2-methylphenyl) benzene-1,4-diamine (MMBD), a psemidine-type homodimer of o-Tol, was detected and identified in an in vitro reaction of o-Tol with S9 mix and in vivo urinary samples of o-Tol-exposed rats. Potent mutagenic, genotoxic, and cytotoxic activities were reported with MMBD, suggesting its involvement in urinary bladder carcinogenesis. However, it remains unknown whether o-Ans is converted to active metabolites to induce DNA damage in a similar manner as o-Tol. In this study, we report that a novel o-Ans metabolite, 2-methoxy-N 4 -(2-methoxyphenyl) benzene-1,4-diamine (MxMxBD), a dimer by head-to-tail binding (p-semidine form), was for the first time identified in o-Ans-exposed rat urine. MxMxBD induced a stronger mutagenicity in N-acetyltransferase overexpressed Salmonella typhimurium strains and potent genotoxicity and cytotoxicity in human bladder carcinoma T24 cells compared with o-Ans. These results suggest that MxMxBD may to some extent contribute toward urinary bladder carcinogenesis. In addition to homodimerization, such as MxMxBD, heterodimerizations were observed when o-Ans was coincubated with o-Tol or aniline (Ani) in in vitro reactions with S9 mix. This study highlights the important consideration of homodimerizations and heterodimerizations of monocyclic aromatic amines, including o-Ans, o-Tol, and Ani, in the evaluation of the combined exposure risk of bladder carcinogenesis.

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Section: Methodsmentioning

confidence: 99%

o-Anisidine Dimer, 2-Methoxy-N⁴-(2-methoxyphenyl) Benzene-1,4-diamine, in Rat Urine Associated with Urinary bladder Carcinogenesis

Kobayashi

Toyoda

Tajima

et al. 2021

Chem. Res. Toxicol.

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“…The secosterols bind to the p53 protein and induce it to misfold and lose the ability to bind to a consensus DNA sequence, signifying that they may contribute to cancers where wild-type inactivation of p53 occurs, such as breast cancer, colon cancer, colon adenoma, and neuroblastoma [ 146 ]. The secosterols and their acidic oxidation products are strongly cytotoxic against various human cell lines, and it was concluded that, during inflammation, cell death caused by them may contribute to further tissue damage and development of disease [ 147 ]. Formation of Schiff's bases between the secosterols and myelin basic protein (MBP) induces myelin instability and might contribute to the onset and progression of multiple sclerosis [ 148 ].…”

Section: The Significance Of Endogenous Singlet Oxygen and Ozone mentioning

confidence: 99%

Endogenous Generation of Singlet Oxygen and Ozone in Human and Animal Tissues: Mechanisms, Biological Significance, and Influence of Dietary Components

Onyango

2016

Oxidative Medicine and Cellular Longevity

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Recent studies have shown that exposing antibodies or amino acids to singlet oxygen results in the formation of ozone (or an ozone-like oxidant) and hydrogen peroxide and that human neutrophils produce both singlet oxygen and ozone during bacterial killing. There is also mounting evidence that endogenous singlet oxygen production may be a common occurrence in cells through various mechanisms. Thus, the ozone-producing combination of singlet oxygen and amino acids might be a common cellular occurrence. This paper reviews the potential pathways of formation of singlet oxygen and ozone in vivo and also proposes some new pathways for singlet oxygen formation. Physiological consequences of the endogenous formation of these oxidants in human tissues are discussed, as well as examples of how dietary factors may promote or inhibit their generation and activity.

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“…( 60 ) Moreover, seco-A-COOH and seco-B-COOH showed strong cytotoxic activities in human acute promyelocytic leukemia HL-60 cells. ( 61 ) Recently, it has been reported that 9-oxononanoyl-secosterol-A and 9-oxononanoyl-secosterol-B—ozonolysis products of cholesteryl-oleate and cholesteryl-linoleate present in human LDL—exert potent cytotoxicity towards HL-60 cells. ( 24 ) Their activity is stronger than other cytotoxic oxysterols exhibiting EC50s of 10–20 µM, which were very similar against various cell lines tested.…”

Section: Chemical and Biological Propertiesmentioning

confidence: 99%

Biochemical properties of cholesterol aldehyde secosterol and its derivatives

Miyoshi

2018

J. Clin. Biochem. Nutr.

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Elevated levels of cholesterol aldehyde, 3β-hydroxy-5-oxo-5,6-secocholestan-6-al (secosterol-A, also called 5,6-secosterol), and its aldolization product (secosterol-B) have been detected in human atherosclerotic plaques and tissues samples of brains affected by neurodegeneration, such as Alzheimer’s disease and Lewy body dementia suggesting that increased formation of these compounds may be associated with inflammation-related diseases. Secosterol-A and secosterol-B, and also further oxidized products seco-A-COOH and seco-B-COOH induce several pro-inflammatory activities in vitro. Accumulating evidences demonstrate that the covalent bindings of these secosterols to target proteins seem to be critical to trigger their pro-inflammatory activities. One of the molecular mechanisms of protein adduct formations is that aldehydic function of secosterol-A and secosterol-B is reactive and form Schiff bases with ε- or N-terminal amino groups of proteins. In other cases, it is recently suggested that Michael acceptor moiety formed by the dehydration of not only secosterol-A and secosterol-B but also seco-A-COOH may react with nucleophilic site on target proteins. In this review, I summarize and provide an overview of formation mechanism of secosterols in in vitro and in vivo, patho- or physiological concentrations in biological and clinical samples, and molecular mechanisms of pro-inflammatory activities of secosterols.

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Cytotoxic Effects of Secosterols and Their Derivatives on Several Cultured Cells

Cited by 14 publications

References 19 publications

o-Anisidine Dimer, 2-Methoxy-N⁴-(2-methoxyphenyl) Benzene-1,4-diamine, in Rat Urine Associated with Urinary bladder Carcinogenesis

o-Anisidine Dimer, 2-Methoxy-N⁴-(2-methoxyphenyl) Benzene-1,4-diamine, in Rat Urine Associated with Urinary bladder Carcinogenesis

Endogenous Generation of Singlet Oxygen and Ozone in Human and Animal Tissues: Mechanisms, Biological Significance, and Influence of Dietary Components

Biochemical properties of cholesterol aldehyde secosterol and its derivatives

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Cytotoxic Effects of Secosterols and Their Derivatives on Several Cultured Cells

Cited by 14 publications

References 19 publications

o-Anisidine Dimer, 2-Methoxy-N4-(2-methoxyphenyl) Benzene-1,4-diamine, in Rat Urine Associated with Urinary bladder Carcinogenesis

o-Anisidine Dimer, 2-Methoxy-N4-(2-methoxyphenyl) Benzene-1,4-diamine, in Rat Urine Associated with Urinary bladder Carcinogenesis

Endogenous Generation of Singlet Oxygen and Ozone in Human and Animal Tissues: Mechanisms, Biological Significance, and Influence of Dietary Components

Biochemical properties of cholesterol aldehyde secosterol and its derivatives

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o-Anisidine Dimer, 2-Methoxy-N⁴-(2-methoxyphenyl) Benzene-1,4-diamine, in Rat Urine Associated with Urinary bladder Carcinogenesis

o-Anisidine Dimer, 2-Methoxy-N⁴-(2-methoxyphenyl) Benzene-1,4-diamine, in Rat Urine Associated with Urinary bladder Carcinogenesis