Relations between strain and gender dependencies of irinotecan toxicity and UGT1A1, CES2 and TOP1 expressions in mice

Toxicol Lett. 2010 Feb 15;192(3):395-401. doi: 10.1016/j.toxlet.2009.11.017. Epub 2009 Nov 29.

Abstract

Irinotecan hydrochloride (CPT-11) can display severe toxicities in individual cancer patients. CPT-11 is bio-activated through CES, detoxified through UGT1A1 and inhibits TOP1. CPT-11 toxicity and UGT1A1, CES2 and TOP1 mRNAs and UGT1A1 protein were determined in male and female C57BL/6, B6D2F1 and B6CBAF1, as potential models for tailoring CPT-11 delivery. CPT-11 was administered intravenously (40-90 mg/kg/day for 4 days at 7h after light onset). The relations between dose and lethal toxicity or body weight loss were steep and similar in C57BL/6 (lethality, p=0.001; weight loss, p=0.002) and B6D2F1 (p=0.01; p=0.03, respectively), but weak in B6CBAF1. Females displayed less toxicity than males (p<0.001). Mean mRNA expression of UGT1A1 was highest in B6CBAF1 (p=0.039) and in females (p<0.001). Both CES2 and TOP1 varied according to strain and gender (p<0.001). The three gene expression data explained the most severe toxicity of CPT-11 in male B6D2F1, but displayed inconsistent relations with toxicity in the other groups. Mean UGT1A1 protein expression was highest in males as compared to females, and so by approximately 8-fold in C57BL/6 as compared to B6D2F1 (p<0.0001). Genetic background and gender significantly altered the molecular prediction of irinotecan toxicity by UGT1A1, CES2 and TOP1 mRNA expressions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Camptothecin / analogs & derivatives*
  • Camptothecin / toxicity
  • Carboxylic Ester Hydrolases / biosynthesis*
  • DNA Topoisomerases, Type I / biosynthesis*
  • Dose-Response Relationship, Drug
  • Female
  • Gene Expression / drug effects
  • Glucuronosyltransferase / biosynthesis*
  • Irinotecan
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Inbred DBA
  • Mice, Inbred Strains
  • Sex Factors
  • Species Specificity

Substances

  • Irinotecan
  • Glucuronosyltransferase
  • Carboxylic Ester Hydrolases
  • Ces2c protein, mouse
  • DNA Topoisomerases, Type I
  • Camptothecin