Proneurotensin/neuromedin N secreted from small cell lung carcinoma cell lines as a potential tumor marker.

Proteins secreted from specific cancer cells have a high potential for use as tumor markers. We identified secreted proteins produced by 15 different carcinoma cell lines grown in serum-free medium using MS/MS. Proneurotensin/neuromedin N (proNT/NMN) was found in conditioned medium from four of seven small cell lung carcinoma cell lines but not from eight nonsmall cell lung carcinoma cell lines. These results indicate proNT/NMN has potential as a specific tumor marker of small cell lung carcinoma.

Induction of hepatic cytochrome P450 isoforms by nicardipine at therapeutic doses in spontaneously hypertensive rats.

Nicardipine hydrochloride (Nic), a calcium channel antagonist, is used for the treatment of hypertension. In the present study, we estimated its effects on the levels and activities of hepatic cytochrome P450 isoforms in spontaneously hypertensive rats given p.o. with Nic at a dose of 0.5, 2.5, 5, or 12.5 mg/kg at 24-hr intervals for 14 days. Therapeutic effects on the development of hypertension were observed at doses of 5 and 12.5 mg/kg/day. Significant increases in the levels of mRNAs and enzyme activities of hepatic P450 isoforms, CYP1A1 and/or CYP1A2, by 14-day repetitive treatment with Nic were observed at lower therapeutic doses, whereas the increase in protein levels for CYP1A2 was observed at a higher therapeutic dose of 12.5 mg/kg/day. Likewise, the activities of hepatic CYP2B and CYP3A subfamily enzymes were increased by the 14-day-treatment of Nic only at a therapeutic dose (12.5 mg/kg/day), whereas their mRNA and protein levels were increased at lower therapeutic doses. To date, the dihydropyridine family, including Nic, has been believed to have inhibitory effects on the activity of various cytochrome P450 enzymes, especially human CYP3A4. However, the present findings demonstrate for the first time that Nic-repetitive treatments at a therapeutic dose result in significant increases in the expressions and activities of hepatic CYP1A, CYP2B, and CYP3A subfamily enzymes. Therefore, the effects of dihydropyridine family on cytochrome P450 enzymes have to be further validated to provide information on its safe and beneficial therapeutic application.

Effects of polychlorinated biphenyls, kanechlor-500, on serum thyroid hormone levels in rats and mice.

Effects of a commercial polychlorinated biphenyls mixture, Kanechlor-500 (KC500), on the levels of serum thyroid hormones such as total thyroxine (T4) and triiodothyronine (T3) were examined comparatively in male Wistar rats and ddy mice. Serum T4 levels were significantly decreased in both rats and mice 4 days after a single ip injection of KC500 (100 mg/kg body weight), whereas decreased levels of T3 were observed in mice but not in rats. In addition, no significant change in the level of serum thyroid stimulating hormone was observed in either rats or mice. Hepatic UDP-glucuronosyltransferases (UDP-GTs) UGT1A1 and UGT1A6, which efficiently mediate glucuronidation of T4 and promote the excretion of the hormones, were induced by KC500 in rats but not in mice. Hepatic microsomal cytochrome P450 (P450) content and the microsomal activity for 7-ethoxy-, 7-pentoxy-, and 7-benzoyloxy-resorufin dealkylations were significantly increased by KC500 in both rats and mice, although the magnitude of increase in the enzyme activities was higher in rats than in mice. The difference in the increase in the activity of microsomal enzymes, including UDP-GT and P450, between KC500-treated rats and mice was not correlated with that in the level of hepatic methylsulfonyl-PCB metabolites. In the present study, we found for the first time that the decrease in serum T4 levels by KC-500 in mice occurred without increase in hepatic UDP-GTs, UGT1A1 and UGT1A6, responsible for T4 glucuronidation. The present findings further suggested that although the decrease in serum T4 levels in KC500-treated rats would occur at least in part through the induction of the UDP-GTs, it might not be dependent on only the increase in the enzymes.