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ToxSci Advance Access published online on July 13, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi252
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received April 29, 2005
Accepted June 30, 2005

Carcinogenicity

Species Differences in the Induction of Hepatocellular DNA Synthesis by Diethanolamine

Lisa M. Kamendulis 1* and James E. Klaunig 1

1 Division of Toxicology, Department of Pharmacology and Toxicology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202 USA

* To whom correspondence should be addressed.
Lisa M. Kamendulis, E-mail: lkamendu{at}iupui.edu


  Abstract

Diethanolamine increased the incidence and multiplicity of liver tumors in the mouse following chronic exposure. Diethanolamine is known to inhibit cellular choline uptake. Since choline deficiency produces tumors in rodents, diethanolamine, through choline depletion, may result in tumor development in rodents. The potential for diethanolamine to function through this mode of action in humans is not known. The present studies examined the effect of diethanolamine (0 - 500 µg/ml) and choline depletion on DNA synthesis and changes in expression of genes involved in cell growth pathways in primary cultures of mouse, rat, and human hepatocytes. In mouse and rat hepatocytes DNA synthesis was increased following treatment with 10 µg/ml diethanolamine and higher (3 to 4-fold over control). In contrast, diethanolamine failed to increase DNA synthesis in human hepatocytes. Incubation of hepatocytes in medium containing reduced choline (1/10 to 1/100 of normal medium; 0.898 mg/L to 0.0898 vs. 8.98 mg/L) increased DNA synthesis (1.6- and 1.8-fold of control in mouse and rat hepatocytes, respectively), however, choline depletion did not induce DNA synthesis in human hepatocytes. Mouse and rat hepatocytes incubated in medium supplemented with 2 to 50-fold excess choline reduced diethanolamine-induced DNA synthesis to control levels or below. Gene expression analysis of mouse and rat hepatocytes following diethanolamine treatment showed increases in genes associated with cell growth, and decreases in expression of genes involved in apoptotic pathways. These results support the hypothesis that choline depletion is central to the mode of action for the induction of rodent hepatic neoplasia by diethanolamine. Furthermore, since diethanolamine treatment or choline depletion failed to induce DNA synthesis in human hepatocytes, these results suggest that humans may not be at risk from the carcinogenic effects of diethanolamine.


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A. N. Bachman, L. M. Kamendulis, and J. I. Goodman
Diethanolamine and Phenobarbital Produce an Altered Pattern of Methylation in GC-Rich Regions of DNA in B6C3F1 Mouse Hepatocytes Similar to That Resulting from Choline Deficiency
Toxicol. Sci., April 1, 2006; 90(2): 317 - 325.
[Abstract] [Full Text] [PDF]


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