Dependence of glucuronidation rate on UDP-glucuronic acid levels in isolated hepatocytes

Abstract

Increasing evidence suggests that variability in hepatic glucuronidation is a critical determinant of mammalian species-specific sensitivity to the Fusarium mycotoxin deoxynivalenol (DON). Concurrently, ongoing work regarding the effects of DON on fish has led to broad classifications concerning species-specific sensitivity (e.g. rainbow trout are highly sensitive to DON and channel catfish are highly tolerant to DON). This study was designed to determine if sensitivity to DON in fish is related to inherent differences in UDP-glucuronosyltransferase (UDPGT) activity and to evaluate if increased dietary digestible starch content could be an effective strategy to increase glucuronidation capacity. Rainbow trout or Nile tilapia (initial average body weight = 21.9 and 8.1 g/fish, respectively) were fed two series (12 or 24% digestible starch) of three diets containing graded levels of naturally occurring DON (0.1, 0.7 and 1.3 ppm) for 10 weeks. Significant linear decreases in weight gain, thermal-unit growth coefficient (TGC, P ≤ .05), feed efficiency (P < .001), whole body crude protein (CP) content (P < .001), retained nitrogen (RN, P ≤ .05) and nitrogen retention efficiency (NRE, P < .01) were associated with increasing levels of DON in rainbow trout regardless of the dietary digestible starch content. There were no significant effects of DON on any of these parameters in Nile tilapia (P > .05) with the exception of a quadratic increase in NRE (P < .01) in fish fed the diets containing 24% digestible starch. The effect of DON on growth performance and nutrient utilization was not altered by the digestible starch content of the diet (P > .05, DON × digestible starch). A significant quadratic decrease (P ≤ .05) in UDPGT activity was associated with increasing levels of DON in rainbow trout fed the diet containing 12% digestible starch, whereas trout and tilapia fed the diet containing 24% digestible starch experienced significant quadratic or linear increases (P ≤ .05) in UDPGT activity, respectively. However, UDPGT activity was approximately 10-fold higher in rainbow trout than in Nile tilapia. This suggests that UDPGT activity is not responsible for the observed species-specific sensitivity to DON or it is not an appropriate biomarker of DON glucuronidation. A significantly higher relative fold expression of CYP1A in tilapia compared to trout (P = .0001) may offer potential opportunity for future study. We demonstrate for the first time that Nile tilapia are unaffected by practically relevant levels of DON which are detrimental to rainbow trout. This study also extends the current knowledge of DON metabolism and represents an important contribution to the development of efficacious nutritional mycotoxin mitigation strategies.