Nicotine metabolism and CYP2A6 allele frequencies in Koreans.

CYP2A6 is a major catalyst of nicotine metabolism to cotinine. Previously, we demonstrated that the interindividual difference in nicotine metabolism is related to a genetic polymorphism of the CYP2A6 gene in Japanese. To clarify the ethnic differences in nicotine metabolism and frequencies of CYP2A6 alleles, we studied nicotine metabolism and the CYP2A6 genotype in 209 Koreans. The cotinine/nicotine ratio of the plasma concentration 2 h after chewing one piece of nicotine gum was calculated as an index of nicotine metabolism. The genotypes of CYP2A6 gene (CYP2A6*1A, CYP2A6*1B, CYP2A6*2, CYP2A6*3, CYP2A6*4 and CYP2A6*5) were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism or allele specific (AS)-PCR. There were ethnic differences in the allele frequencies of CYP2A6*1A, CYP2A6*1B, CYP2A6*4 and CYP2A6*5 between Koreans (45.7%, 42.8%, 11.0% and 0.5%, respectively) and Japanese (42.4%, 37.5%, 20.1% and 0%, respectively, our previous data). Similar to the Japanese, no CYP2A6*2 and CYP2A6*3 alleles were found in Koreans. The homozygotes of the CYP2A6*4 allele (four subjects) were completely deficient in cotinine formation, being consistent with the data among Japanese. The heterozygotes of CYP2A6*4 tended to possess a lower metabolic ratio (CYP2A6*1A/CYP2A6*4, 4.79 +/- 3.17; CYP2A6*1B/CYP2A6*4, 7.43 +/- 4.97) than that in subjects without the allele (CYP2A6*1A/CYP2A6*1A, 7.42 +/- 6.56; CYP2A6*1A/CYP2A6*1B, 9.85 +/- 16.12; CYP2A6*1B/CYP2A6*1B, 11.33 +/- 9.33). The subjects who possess the CYP2A6*1B allele appeared to show higher capabilities of cotinine formation. It was confirmed that the interindividual difference in nicotine metabolism was closely related to the genetic polymorphism of CYP2A6. The probit plot of the metabolic ratios in Koreans (8.73 +/- 11.88) was shifted to a higher ratio than that in the Japanese (3.78 +/- 3.09). In each genotype group, the Korean subjects revealed significantly higher metabolic ratios than the Japanese subjects. The ethnic difference in cotinine formation might be due to environmental and/or diet factors as well as genetic factors.

NMDA receptor and NO mediate ET-1-induced behavioral and cardiovascular effects in periaqueductal gray matter of rats.

Endothelin-1 (ET-1), a novel and potent vasoconstrictor in blood vessel, is known to have some functions in the rat central nervous system (CNS). In order to investigate the central functions of ET-1, ET-1 was administered to the periaqueductal gray area (PAG) of anesthetized rats to induce barrel rolling and increase the arterial blood pressure (ABP). ET-1 had a modulatory effect on central cardiovascular and behavioral control. The selective N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (3 micromol/kg, i.p.) blocked the ET-1 induced responses, and both the nitric oxide synthase (NOS) inhibitor L-NAME (N-nitro-L-arginine methylester 1 mmol/rat) and the nitric oxide (NO) scavenger hemoglobin (15 nmol/rat) had similar effects in reducing the ET-1 (10 pmol/rat)-induced behavioral changes and ABP elevation. However, NO donor sodium nitroprusside (SNP 10 microg, 1 microg/rat) decreased the ET-1 induced ABP elevation, and recovered the ET-1-induced barrel rolling effect that was reduced by MK-801. These results suggest that ET-1 might have neuromodulatory functions such as ABP elevation and barrel rolling induction in the PAG of the rats via the NMDA receptor and NO.