Abstract：
:Increasing incidence of multidrug-resistant bacteria presents an imminent risk to global health. Polymyxins are 'last-resort' antibiotics against Gram-negative 'superbugs'; however, nephrotoxicity remains a key impediment in their clinical use. Molecular mechanisms underlying this nephrotoxicity remain poorly defined. Here, we examined the pathways which led to polymyxin B induced cell death in vitro and in vivo. Human proximal tubular cells were treated with polymyxin B (12.5-100 μM) for up to 24 h and showed a significant increase in micronuclei frequency, as well as abnormal mitotic events (over 40% in treated cells, p < 0.05). Time-course studies were performed using a mouse nephrotoxicity model (cumulative 72 mg/kg). Kidneys were collected over 48 h and investigated for histopathology and DNA damage. Notable increases in γH2AX foci (indicative of double-stranded breaks) were observed in both cell culture (up to ~ 44% cells with 5+ foci at 24 h, p < 0.05) and mice treated with polymyxin B (up to ~ 25%, p < 0.05). Consistent with these results, in vitro assays showed high binding affinity of polymyxin B to DNA. Together, our results indicate that polymyxin B nephrotoxicity is associated with DNA damage, leading to chromosome missegregation and genome instability. This novel mechanistic information may lead to new strategies to overcome the nephrotoxicity of this important last-line class of antibiotics.
journal_name
Arch Toxicoljournal_title
Archives of toxicologyauthors
Yun B,Zhang T,Azad MAK,Wang J,Nowell CJ,Kalitsis P,Velkov T,Hudson DF,Li Jdoi
10.1007/s00204-018-2192-1subject
Has Abstractpub_date
2018-07-01 00:00:00pages
2259-2271issue
7eissn
0340-5761issn
1432-0738pii
10.1007/s00204-018-2192-1journal_volume
92pub_type
杂志文章abstract：:Mouse liver CYP2A5 is induced by several structurally unrelated compounds. In intact mouse liver, pyrazole (PYR) and 4-hydroxypyrazole (4-OH) induce selectively the expression of CYP2A5 while expression of other CYPs is decreased. In this study we exposed mouse primary hepatocytes to PYR, 4-OH, 4-methylpyrazole (4Me; ...
journal_title：Archives of toxicology
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journal_title：Archives of toxicology
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journal_title：Archives of toxicology
pub_type： 杂志文章
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journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/BF02072035
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pub_type： 杂志文章
doi：10.1007/s00204-002-0350-x
更新日期：2002-08-01 00:00:00
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journal_title：Archives of toxicology
pub_type： 杂志文章
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journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s002040050001
更新日期：2000-01-01 00:00:00
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journal_title：Archives of toxicology
pub_type： 杂志文章,评审
doi：10.1007/s00204-020-02770-x
更新日期：2020-06-01 00:00:00
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journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s002040050067
更新日期：1994-01-01 00:00:00
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journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s00204-018-2159-2
更新日期：2018-04-01 00:00:00
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journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s00204-004-0541-8
更新日期：2004-06-01 00:00:00
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journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s002040050593
更新日期：1999-03-01 00:00:00
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journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s00204-005-0016-6
更新日期：2006-02-01 00:00:00
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journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/BF00340977
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journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/BF00368231
更新日期：1978-01-25 00:00:00
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journal_title：Archives of toxicology
pub_type： 杂志文章,评审
doi：10.1007/s00204-016-1757-0
更新日期：2016-08-01 00:00:00
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journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s00204-015-1527-4
更新日期：2016-04-01 00:00:00
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journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s00204-012-0979-z
更新日期：2013-04-01 00:00:00
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journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s00204-010-0603-z
更新日期：2011-06-01 00:00:00
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journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/BF00310332
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journal_title：Archives of toxicology
pub_type： 杂志文章,评审
doi：10.1007/s00204-011-0705-2
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journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s00204-006-0057-5
更新日期：2006-07-01 00:00:00
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journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/BF00292616
更新日期：1985-10-01 00:00:00
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journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s002040100264
更新日期：2001-10-01 00:00:00
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journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s00204-017-2002-1
更新日期：2017-08-01 00:00:00
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journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/s002040050677
更新日期：1999-09-01 00:00:00
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journal_title：Archives of toxicology
pub_type： 杂志文章
doi：10.1007/BF00340534
更新日期：1976-12-17 00:00:00
