Systemic and local release of inflammatory cytokines regulates hepatobiliary excretion of 99mTc-mebrofenin.
OBJECTIVE
Imaging agents capable of providing cell compartment-specific information will facilitate studies of pathophysiological mechanisms, natural history of diseases, and therapeutic development. To demonstrate the effects of liver injury on the disposal of the organic anion mebrofenin, we performed animal studies.


METHODS
Acute liver injury was induced in Fischer 344 rats with 0.25-1 ml/kg single doses of carbon tetrachloride followed by studies of animals over 4 weeks. The liver injury was analyzed by blood tests and histological grading. Additional rats were treated with lipopolysaccharide, interleukin-6 or tumor necrosis factor-alpha to activate inflammatory events. Hepatic clearance of Tc-mebrofenin was studied with dynamic imaging and fractional retention after 60 min of peak hepatic mebrofenin activity was determined.


RESULTS
In healthy rats, only 24+/-2% of peak mebrofenin activity was retained in the liver after 60 min. By contrast, 24 h after carbon tetrachloride, virtually all mebrofenin activity was retained in the liver (P<0.001). Three weeks were required for mebrofenin excretion to become normal after carbon tetrachloride administration. In this situation, we found that Kupffer cell activity was increased. In addition, the abnormality in mebrofenin excretion was reproduced by lipopolysaccharide, which activates Kupffer cells. Moreover, mebrofenin excretion was highly sensitive to interleukin-6 and/or tumor necrosis factor-alpha, which help mediate the Kupffer cell response.


CONCLUSIONS
Hepatobiliary excretion of mebrofenin was affected rapidly and over an extended period by inflammatory cytokines released after liver injury. The remarkable sensitivity of mebrofenin excretion to cytokines suggests that Tc-mebrofenin imaging will be helpful for assessing cytokine-mediated liver inflammation.
Joseph
Brigid
B
Department of Medicine and Pathology, Marion Bessin Liver Research Center, Jack and Pearl Resnick Campus, North Shore-Long Island Jewish Health System Campus, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Bhargava
Kuldeep K
KK
Tronco
Gene G
GG
Palestro
Christopher J
CJ
Gupta
Sanjeev
S
D000814:Aniline Compounds; D000818:Animals; D016207:Cytokines; D005998:Glycine; D007098:Imino Acids / Q000097:blood* / Q000493:pharmacokinetics*; D007155:Immunologic Factors / Q000378:metabolism*; D008099:Liver / Q000000981:diagnostic imaging / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D015609:Organotechnetium Compounds / Q000097:blood* / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000097:blood / Q000493:pharmacokinetics; D051381:Rats; D011916:Rats, Inbred F344
D000814:Aniline Compounds; D016207:Cytokines; D007098:Imino Acids; D007155:Immunologic Factors; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; C034837:technetium Tc 99m mebrofenin; D005998:Glycine