Go Fish! Hepatic Uptake of Clinical Hepatospecific Gadolinium-Based MRI Contrast Agents in Zebrafish is Similar to Humans.

Abstract

Purpose: Zebrafish are a useful organism for investigating liver disease due to their genetic similarities with humans, particularly in genes associated with liver function. It has been posited that liver function can be assessed non-invasively by MRI, measuring the hepatic accumulation of gadolinium-based contrast agents (GBCAs). We characterized the hepatic uptake of various hepatospecific and non-hepatospecific clinical GBCAs in zebrafish.

Procedures: To introduce GBCAs systemically, zebrafish swam for 30 min in water containing 5 mM of various clinical hepatospecific or non-hepatospecific GBCAs. Fish were then sacrificed and underwent 3D, T1-weighted, high-resolution MRI at 9.4 T. In vitro MRI and transport studies of the same GBCAs were conducted in HEK293T cells transiently expressing OATP1D1, OATP1B2 and OATP1B3.

Results: T1-weighted ex-vivo MRI of zebrafish showed hyperintensity in the liver, gall bladder, bile ducts, and intestine for fish swimming in gadoxetate, but not for in gadobenate nor gadoterate. In vitro cell experiments confirm that gadoxetate but not gadobenate is efficiently transported by OATP1D1.

Conclusion: Zebrafish liver accumulates gadoxetate but not gadobenate via OATP1D1 transport, among the two clinical hepatospecific MRI GBCAs, and also does not accumulate gadoterate, a non-hepatospecific GBCA. This pattern of GBCA hepatic uptake is similar to humans but differs from all other non-primates reported, which exhibit high hepatic uptake of both gadoxetate and gadobenate.