This study was conducted to assess whether the genotypec frequency of S-mephenytoin 4'-hydroxylase CYP2C19 is affected by hepatic carcinoma. Method: Liver samples were donated from Japanese hepatic cancer patients who received partial hepatectomy; fifteen had hepatocellular carcinoma (HCC) and 22 had metastatic hepatic cancer (MC) . Individual CYP2C19 genotypes were determined by PCR-based amplification method followed by restriction fragment length analysis. Hepatic microsomal CYP2C19 activity was determined by S-mephenytoin 4'-hydroxylation (S-MP 4'-OH) . A higher frequency of CYP2C19 gene mutation both in exon 4 and 5 was observed in MC patients compared to HCC patients. S-MP 4'-OH was relatively well correlated to the genotype in the samples from MC patients; most samples with CYP2C19 *1/*1 showed comparable activity to that of healthy subjects reported although the samples with mutations showed lower activity. In contrast, declined activity of the enzyme was observed in HCC samples in spite of the existence of mutations. These results suggest that low activity of CYP2C19 in MC patients was due to the enzyme deficiency caused by mutation of the CYP2C19 gene. In addition, a CYP2C19 deficiency might reflect the potentials of carcinoma metastasis of the liver.

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Blood flow in the lower leg was measured following administration of elcatonin (a synthetic derivative of eel calcitonin) . The subjects were 28 men and women who had been hospitalized for the treatment of osteoporosis, and all were to receive elcatonin. All subjects consented to the measurement of blood flow in the lower leg. Eight healthy female volunteers were assigned to the control group. Blood flow was measured prior to and six hours following administration of elcatonin. Both flow and mass increased significantly following administration of elcatonin. Both flow and mass measurements prior to administration of elcatonin were put in order according to value, starting with the lowest; the first 14 measurements were grouped together as the low measurement groups while the remaining measurements the formed the high measurement groups. Both flow and mass increased significantly in the low measurement groups. These results demonstrate that elcatonin increases blood flow in areas of decreased flow while maintaining existing blood flow in areas where the flow is normal. It is known that calcitonin preparations alleviate pain and inhibit bone resorption. The results of this study suggest that they also increase blood flow and dilate blood vessels where there is decreased blood flow.

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Our recent studies indicate that urotensin II (UII), the most potent vasoconstrictor peptide identified to date, potentiates human macrophage foam cell formation and vascular smooth muscle cell proliferation, and UII levels are increased in the plasma of hypertensive patients with carotid atherosclerotic plaques. Here, we investigated the enhancing effect of UII on atherosclerosis in apolipoprotein E (apoE) - deficient mice and its suppression by 4-aminoquinoline, a non-peptide UII receptor (UT) -selective antagonist. UII, UII + 4-aminoquinoline, or vehicle was infused for 4 weeks through an osmotic mini-pump into 9-week-old apoE-deficient mice on a high-fat diet. Aortic atherosclerosis and foam cell formation in exudate peritoneal macrophages were examined. Atherosclerotic lesions as well as plasma levels of UII, reactive oxygen species (ROS), and oxidized low-density lipoprotein (oxLDL) and oxLDL-induced foam cell formation were significantly greater in UII-infused mice than in the vehicle-infused controls. Western blotting analysis showed increased expressions of scavenger receptors (CD36 and SR-A) and acyl-CoA: cholesterol acyltransferase 1 (ACATI) in these macrophages. Increases in these parameters were significantly reduced by addition of 4-aminoquinoline. In apoE-deficient mice even without UII infusion, the treatment with 4-aminoquinoline for 8 weeks significantly prevented the development of atherosclerotic lesions. Our results suggest that an increased plasma UII level stimulates oxLDL and ROS production and macrophage foam cell formation via increased expressions of CD36, SR-A, and ACAT1, contributing to the development of atherosclerosis in apoE-deficient mice. UT antagonism may provide a therapeutic strategy against atherosclerosis.

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