title: Strain- and sex-dependent circadian changes in abcc2 transporter expression: implications for irinotecan chronotolerance in mouse ileum.
abstract: BACKGROUND
  ATP-binding cassette transporter abcc2 is involved in the cellular efflux of irinotecan. The drug is toxic for mouse ileum, where abcc2 is highly expressed. Here, we investigate whether circadian changes in local abcc2 expression participate in the circadian rhythm of irinotecan toxicity for ileum mucosa, and further assess whether genetic background or sex modify this relation.
  
  
  RESULTS
  Ileum mucosa was obtained every 3-4 h for 24 h in male and female B6D2F(1) and B6CBAF(1) mice synchronized with light from Zeitgeber Time (ZT)0 to ZT12 alternating with 12 h of darkness. Irinotecan (50 mg/kg i.v. daily for 4 days) was administered at the sex- and strain-specific times corresponding to least (ZT11-15) or largest drug-induced body weight loss (ZT23-03-07). Abcc2 expression was determined with qRT-PCR for mRNA and with immunohistochemistry and confocal microscopy for protein. Histopathologic lesions were graded in ileum tissues obtained 2, 4 or 6 days after treatment. Two- to six-fold circadian changes were demonstrated for mRNA and protein mean expressions of abcc2 in mouse ileum (p<0.05). ZT12 corresponded to high mRNA and protein expressions, with circadian waveforms differing according to genetic background and sex. The proportion of mice spared from ileum lesions varied three-fold according to irinotecan timing, with best tolerability at ZT11-15 (p = 0.00003). Irinotecan was also best tolerated in males (p = 0.05) and in B6CBAF(1) (p = 0.0006).
  
  
  CONCLUSIONS
  Strain- and sex-dependent circadian patterns in abcc2 expressions displayed robust relations with the chronotolerance of ileum mucosa for irinotecan. This finding has strong potential implications for improving the intestinal tolerability of anticancer drugs through circadian delivery.
authors.affiliation: INSERM, U776 Rythmes Biologiques et Cancers, Hôpital Paul Brousse, Villejuif, France.
authors.forename: Alper
authors.initials: A
authors.lastname: Okyar
authors.forename: Enza
authors.initials: E
authors.lastname: Piccolo
authors.forename: Constance
authors.initials: C
authors.lastname: Ahowesso
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Filipski
authors.forename: Virginie
authors.initials: V
authors.lastname: Hossard
authors.forename: Catherine
authors.initials: C
authors.lastname: Guettier
authors.forename: Rosanna
authors.initials: R
authors.lastname: La Sorda
authors.forename: Nicola
authors.initials: N
authors.lastname: Tinari
authors.forename: Stefano
authors.initials: S
authors.lastname: Iacobelli
authors.forename: Francis
authors.initials: F
authors.lastname: Lévi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives*; D002940:Circadian Rhythm; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D000077146:Irinotecan; D008297:Male; D051379:Mice; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012727:Sex Characteristics; D013045:Species Specificity
chemical_list: D000970:Antineoplastic Agents; D002166:Camptothecin; D000077146:Irinotecan; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger