Different Renal Chronotoxicity of Bromobenzene and Its Intermediate Metabolites in Mice

Yoshioka, Hiroki; Tominaga, Sarah; Nishikawa, Mai; Shinohara, Yasuro; Nakao, Makoto; Yoshikawa, Masae; Maeda, Tohru; Miura, Nobuhiko

doi:10.1248/bpb.b20-00694

Cited by 8 publications

(7 citation statements)

References 13 publications

(22 reference statements)

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“…We have developed the chronotoxicology considering the relationship between injection time and the toxic severity of medicines or chemicals. [8][9][10][11][12][13] For example, we demonstrated that streptomycin, which induces renal toxicity, showed clear diurnal validation in mice. 12) Streptomycin induced renal injury during the dark phase, but did not induce any damage when administrated during the light phase.…”

Section: Introductionmentioning

confidence: 78%

“…9) Additionally, injection of BB-metabolites such as 4-bromocatechol (4-BrCA) confirmed renal dysfunction during the dark phase. 11) Although our previous studies have shown that BB and BB-metabolites exhibited diurnal variation, the cellular molecule(s) involving this chronotoxicity have not been evaluated. Therefore, in the present study, we investigated the diurnal mechanism of 4-BrCA-induced renal toxicity in MuRTE61 Biol.…”

Section: Introductionmentioning

confidence: 99%

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Involvement of Bmal1 and Clock in Bromobenzene Metabolite-Induced Diurnal Renal Toxicity

Yoshioka

Yokota²,

Tominaga

et al. 2023

Biological & Pharmaceutical Bulletin

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Circadian rhythms are endogenous oscillators that regulate 24 h behavioral and physiological processes. Our previous investigation demonstrated that bromobenzene metabolite (4-bromocatechol: 4-BrCA) exhibited chronotoxicity (i.e., the nephrotoxicity induced by 4-BrCA was observed during the dark phase, while not observed at light phase in mice). However, the molecular mechanism is still unknown. The aim of the present study is to investigate the cellular molecule(s) involved in the 4-BrCA-induced nephrotoxicity using mouse renal cortex tubular cell lines (MuRTE61 cells). We found that 4-BrCA showed dose dependent (0.01-1 mM) cell proliferation defect in MuRTE61 cells. By treating with 0.03 mM 4-BrCA, we demonstrated that major clock genes (Bmal1, Clock, Cry1, Cry2, Per1, and Per2) were significantly downregulated. Interestingly, the expression levels of two genes, Bmal1 and Clock, continued to decrease after 3 h of treatment with 4-BrCA, while Cry1, Per1, and Per2 were unchanged until 24 h of treatment. Moreover, BMAL1 and CLOCK levels are higher at light phase. We speculated that BMAL1 and CLOCK might function defensively against 4-BrCA-induced nephrotoxicity since the expression levels of Bmal1 and Clock were rapidly decreased. Finally, overexpression of Bmal1 and Clock restored 4-BrCA-induced cell proliferation defect in MuRTE61 cells. Taken together, our results suggest that Bmal1 and Clock have protective roles against 4-BrCA-induced nephrotoxicity.

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Section: Introductionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Involvement of Bmal1 and Clock in Bromobenzene Metabolite-Induced Diurnal Renal Toxicity

Yoshioka

Yokota²,

Tominaga

et al. 2023

Biological & Pharmaceutical Bulletin

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“…Immunoblotting. Extraction of KD cells was conducted according to our previous literature (Yoshioka et al, 2021c(Yoshioka et al, , 2022. Protein samples (10 μg) were subjected to 10% SDS-PAGE and transferred to a polyvinylidene difluoride membrane.…”

Section: Methodsmentioning

confidence: 99%

Sasa veitchii extracts protect phenytoin-induced cell proliferation inhibition in human lip mesenchymal cells through modulation of miR-27b-5p

et al. 2023

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A cleft lip, with or without a cleft palate, is a common birth defect caused by environmental factors or genetic mutations. Environmental factors, such as pharmaceutical exposure in pregnant women, are known to induce cleft lip, with or without cleft palate in the child. This study aimed to investigate the protective effect of Sasa veitchii extract (SE) on phenytoin-induced inhibition of cell proliferation in human lip mesenchymal cells (KD cells) and human embryonic palatal mesenchymal cells (HEPM cells). We demonstrated that cell proliferation was inhibited by phenytoin in a dose-dependent manner in both KD and HEPM cells. Co-treatment with SE restored phenytoin-induced toxicity in KD cells but did not protect HEPM cells against phenytoin-induced toxicity. Several microRNAs (miR-27b, miR-133b, miR-205, miR-497-5p, and miR-655-3p) is reported to associate with cell proliferation in KD cells. We measured the seven kinds of microRNAs (miR-27b-3p, miR-27b-5p, miR-133b, miR-205-3p, miR-205-5p, miR-497-5p, and miR-655-3p) and found that SE suppressed miR-27b-5p induced by phenytoin in KD cells. Furthermore, co-treatment with SE enhanced the expression of miR-27b-5p downstream genes (PAX9, RARA, and SUMO1). These results suggest that SE protects phenytoin-induced cell proliferation inhibition by modulating miR-27b-5p.

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“…For instance, we previously demonstrated that the industrial solvent bromobenzene induces more severe toxicity during the light phase than during the dark phase [17]. Bromobenzene metabolites, such as 4-bromocatechol, confirmed renal dysfunction during the dark phase [19]. Additionally, we evaluated the chronotoxicology of seven metals (Hg, Pb, Ni, Cr, Cu, Zn, and Fe) [18] in mice.…”

Section: Introductionmentioning

confidence: 91%

“…We studied the relationship between the timing of med-icine or chemical administration and the severity of toxicity as chronotoxicology [16][17][18][19][20][21]. For instance, we previously demonstrated that the industrial solvent bromobenzene induces more severe toxicity during the light phase than during the dark phase [17].…”

Section: Introductionmentioning

confidence: 99%

Copper-induced diurnal hepatic toxicity is associated with Cry2 and Per1 in mice

Tominaga,

Yoshioka,

Yokota

et al. 2023

Environ Health Prev Med

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Background: This study aimed to investigate diurnal variations in copper-induced hepatic toxicity and the molecular mechanisms underlying this chronotoxicity. Methods: Male C57BL/6J mice were intraperitoneally injected with copper chloride (CuCl 2 ) at zeitgeber time 2 (ZT2) or 14 (ZT14), twice per week for 5 or 8 weeks. Seventy-two hours after the final CuCl 2 injection, the mice were euthanized, and plasma samples were collected. The livers and kidneys were collected and weighed. In vitro experiments were performed to assess cell viability and fluctuations in clock gene expression levels in Hepa1-6 cells after CuCl 2 treatment. We examined copper homeostasis-and apoptosisrelated genes under clock genes overexpression. Results: Repeated CuCl 2 administration for 8 weeks resulted in more severe toxicity at ZT14 compared to ZT2. CuCl 2 administration at ZT14 elevated plasma aspartate aminotransferase, hepatic tumor necrosis factor-¡, and interleukin-6 for 5 weeks, whereas the toxic effects of CuCl 2 administration at ZT2 were weaker. Moreover, CuCl 2 treatment inhibited Hepa1-6 cell viability in a dose-dependent manner. We observed increased expression of three clock genes (Ciart, Cry2, and Per1) after CuCl 2 treatment. Among them, overexpression of Cry2 and Per1 accelerated CuCl 2 -induced inhibition of Hepa1-6 cell viability. Moreover, we found that the overexpression of Cry2 and Per1 regulates cleaved caspase-3 by modulating the copper transporter genes ATP7B and CTR1. Conclusion: These results suggest that CuCl 2 -induced diurnal toxicity is associated with Cry2 and Per1 expression through the regulation of copper transporter genes in mice.

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Different Renal Chronotoxicity of Bromobenzene and Its Intermediate Metabolites in Mice

Cited by 8 publications

References 13 publications

Involvement of <i>Bmal1</i> and <i>Clock</i> in Bromobenzene Metabolite-Induced Diurnal Renal Toxicity

Involvement of <i>Bmal1</i> and <i>Clock</i> in Bromobenzene Metabolite-Induced Diurnal Renal Toxicity

<i>Sasa veitchii</i> extracts protect phenytoin-induced cell proliferation inhibition in human lip mesenchymal cells through modulation of <i>miR-27b-5p </i>

Copper-induced diurnal hepatic toxicity is associated with <i>Cry2</i> and <i>Per1</i> in mice

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