|Voss, Kenneth - Ken|
|Merrill, Jr, A|
Submitted to: Toxicologist
Publication Type: Abstract Only
Publication Acceptance Date: 12/15/2001
Publication Date: 3/17/2002
Citation: Voss, K.A., Humpf, H., Sullards, M., Allgood, K., Hartl, M., Riley, R.T., Merrill, Jr, A.H. 2002. IN VIVO FORMATION OF CERAMIDE-LIKE N-ACYLATED AMINOPENTOLS FROM HYDROLYZED FUMONISIN B1. Toxicologist. 66:2. Interpretive Summary: Abstract only
Technical Abstract: Fumonisins are toxic and carcinogenic mycotoxins found in corn-based foods. Alkaline conditions such as those used for making masa from corn convert fumonisins to their hydrolyzed forms. The subchronic liver and kidney effects of hydrolyzed fumonisin B1 (HFB1), also referred to as aminopentol (AP1), and fumonisin B1 (FB1) in rodents are similar and HFB1, like FB1, inhibits the enzyme ceramide synthase. Fumonisin metabolism has not been shown. However, formation of the ceramide-like compound N-palmitoyl aminopentol 1 (PAP1) from palmitoyl-CoA and HFB1 by rat liver microsomes in vitro has recently been reported. PAP1 was more toxic (using cell death as the endpoint) than FB1 or HFB1 to cultured HT29 human colonic cells. To determine if PAP1 or other N-acylated aminopentols (AAP1) are formed in vivo, male rats (n=3) were given 52, 115 or 230 HFB1/day (ip injection) for 5 days. Controls (n=2) received the saline vehicle. Two rats/group were euthanized 2 hours after the last dose. Remaining animals were killed 3 weeks later. HFB1 was not toxic and did not cause microscopic kidney or liver lesions. It did, however, partially inhibit ceramide synthase, as shown by increased sphinganine and sphingosine concentrations in liver and kidney. Mass spectrometric analysis revealed a series of AAP1 compounds in liver of the HFB1-exposed rats. The metabolites' acyl groups ranged in length from C16 (PAP1) to C24. C24 compounds were most abundant, ranging from 0.5-2.4 nmole/g tissue, while up to 0.3 nmole/g of the other metabolites were found. Lesser amounts were detected in kidney and blood. The AAP1 metabolites were not persistent; none were detected 3 weeks after the final dose. These findings demonostrate that HFB1 is a substrate for ceramide synthase in vivo. The effects of AAP1 metabolites in animals chronically exposed to HFB1 warrant investigation.