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Biomedical subjects

A H Merrill

Publications and source records attributed to A H Merrill.

149 records · Page 9Linked to original sources
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The fasting B6 vitamer profile and response to a pyridoxine load in normal and cirrhotic subjects.

This study established the fasting plasma and urine profiles of vitamin B6 in cirrhotics and assessed the response to an oral dose of pyridoxine. High-performance liquid chromatography was used to measure all vitameric coenzymatic and degradatory forms. In 31 patients with cirrhosis and 15 healthy controls, fasting plasma and 24-hr urine collection showed: plasma pyridoxal-5'-phosphate, the biologically active form, was significantly (p less than 0.001) reduced in cirrhotics (mean +/- S.D.: 5.7 +/- 3.2 ng per ml) compared to normals (14.2 +/- 7.5 ng per ml); plasma pyridoxal was detected in more cirrhotics (48%) than normals (28%); pyridoxic acid, the end catabolite, was significantly (p less than 0.05) lower in plasma of cirrhotics compared to normals, but 24-hr urine excretion was not different. Administration of 25 mg of pyridoxine to 7 cirrhotics and 5 normals showed the following plasma changes: pyridoxine rapidly peaked at 30 min and was totally cleared from plasma by 3 hr; plasma pyridoxal and pyridoxic acid increased in parallel up to 40-fold over baseline by 1 to 2 hr and rapidly fell toward baseline by 8 hr, and plasma pyridoxal-5'-phosphate, in contrast, increased significantly (p less than 0.05) from baseline by 60 min and was maintained above normal for 24 hr. The area under the plasma concentration vs. time curve (AUC) for pyridoxal-5'-phosphate was significantly (p less than 0.05) less for the cirrhotics than normals and showed a significant negative correlation to hepatocyte function and blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
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Characterization of cell-cycle arrest by fumonisin B1 in CV-1 cells.

Fusarium moniliforme is a widespread fungal pathogen which primarily infects corn, but can also infect rice or wheat. Fusarium moniliforme produce several mycotoxins, the most prominent of which is called fumonisin B1 (FB1). Epidemiological studies have indicated that ingestion of fumonisins correlates with a higher incidence of oesophageal cancer in Africa and China. Fumonisins also cause a neurodegenerative disease in horses, induce hepatic cancer in rats, are nephrotoxic in rats, or cause pulmonary oedema in swine. Structurally, fumonisins resemble sphingolipids and can alter sphingolipid biosynthesis. suggesting that sphingolipid alterations play a role in disease and carcinogenesis. Previous studies determined that FB1 blocked cell-cycle progression in CV-1 cells but not COS-7 cells. Herein, we have examined the effects that FB1 treatment has on cell-cycle regulatory proteins. Our studies established that FB1 treatment of CV-1 cells, but not COS-7 cells, leads to dephosphorylation of the retinoblastoma (Rb) protein. Cyclin dependent kinase 2 (CDK2) activity was repressed five- to 10-fold and cyclin E protein levels were lower in CV-1 cells after fumonisin treatment. Two CDK inhibitors, Kip1 and Kip2, were induced within 3 hours after fumonisin treatment of CV-1 cells, suggesting these two proteins mediate cell-cycle arrest induced by FB1. This mycotoxin caused large increases in sphinganine within 3 hours after addition of FB1. As sphingoid bases are known to induce Rb phosphorylation, this increase in sphinganinie might be the stimulus for the suppression of cyclin dependent kinase activities via Kip1 and Kip2. The ability of FB1 to accumulate sphingosine or sphinganine and arrest the cell cycle in some cells but not others may play an important role in carcinogenesis or disease.

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Synthesis of N-(4'-pyridoxyl)sphingosine and its uptake and metabolism by isolated cells.

N-(4'-pyridoxyl)sphingosine was synthesized and characterized as a stable compound for specialized delivery of a bioactive lipid. It was found to be facilely taken up by hepatocytes although by a mechanism more typical for lipids than the one used by natural vitamin B6. Some of the N-(4'-pyridoxyl)sphingosine was metabolically acted upon inside the cell to release pyridoxal 5'-phosphate and sphingosine, but formation of pyridoxal 5'-phosphate from the synthetic compound was poor compared with natural vitamin forms of B6, which may partly be due to entrapment within cell membranes and to constraints at the level of cytosolic pyridoxal kinase which is responsible for phosphorylation of the vitamin. Unlike the parent long-chain base, the B6 conjugate was not particularly cytotoxic. Furthermore, the compound was neither an activator nor inhibitor of the respiratory burst of human neutrophils. These findings identify N-(4'-pyridoxyl)sphingosine as an interesting tool for studies of the cellular transport, metabolism, and functions of both vitamin B6 and sphingosine.

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