In vivo Evaluation of Coumarin and Nicotine as Probe Drugs to Predict the Metabolic Capacity of CYP2A6 Due to Genetic Polymorphism in Thais

Abstract

The association between the distribution characteristics of CYP2A6 catalytic activities toward nicotine and coumarin, and the frequency distribution of CYP2A6 variant alleles reported was estimated in 120 healthy Thais. The distributions of the subjects as classified by the amounts of 7-hydroxycoumarin (7-OHC) excreted in the urine and by cotinine/nicotine ratio in the plasma were clearly bimodal. However, the numbers of apparently poor metabolizers for coumarin and nicotine were different. The inter-individual variability in the in vivo dispositions of coumarin and nicotine closely related to the CYP2A6 genetic polymorphism. There was a close correlation between the rate of 7-OHC excretion in the urine and cotinine/nicotine ratio in the plasma among subjects (R=0.92, p<0.001). The frequency of CYP2A6 allele found in the present study was: CYP2A6*1A=32% (95% CI, 22.1-39.4%), CYP2A6*1B=27% (95% CI, 19.4-33.5%), CYP2A6*9=20% (95% CI, 17.6-23.3%), CYP2A6*4=14% (95% CI, 9.6-17.8%), CYP2A6*7=5% (95% CI, 3.7-9.4%), CYP2A6*10=2% (95% CI, 0.8-5.1%). Subjects having CYP2A6*1A/*1B were found to have a higher rate of 7-OHC excretion, as well as a higher cotinine/nicotine ratio in the plasma compared with those of the other genotypes. In contrast, subjects with CYP2A6*4/*7 and CYP2A6*7/*7 almost lacked any cotinine formation, whereas urinary 7-OHC was still detectable. CYP2A6*9 allele clearly resulted in reduced enzyme activities. Despite the absence of the homozygote for CYP2A6*10 allele, the presence of CYP2A6*10 allele significantly decreased the enzyme activities. The results of the present study demonstrate that in vivo phenotyping of CYP2A6 using nicotine and coumarin are not metabolically equivalent. Nicotine is a better probe according to its specificity, while coumarin is still valuable to be used for a routine CYP2A6 phenotyping since the test employs a non-invasive method.

Genotoxic biomonitoring of tobacco farmers: Biomarkers of exposure, of early biological effects and of susceptibility

“…Our study recorded evidence that nicotine exposure (leaf harvest group) was associated with significantly higher NPB in the CYP2A6*1/*1 individuals. CYP2A6*9 subjects possessed lower rates of coumarin and nicotine metabolism [67]. Maybe the normal metabolism of nicotine can be inducing DNA damage.…”

Distribution of polymorphic variants of CYP2A6 and their involvement in nicotine addiction

“…However, in African Americans, Ghanaians and Namibians the frequencies were between 66.5-80.5 % (Gyamfi et al, 2005[45]; Nakajima et al, 2004[95]; Takeshita et al, 2006[129]) while it was the opposite in Asians. Asians living in the UK report a frequency of 64.1 % while East and South Asian populations (Chinese, Japanese, Korean, Malaysian, Thai, Indian, Bangladeshi and Sri Lankan) report a frequency of 27-52 % (Ariyoshi et al, 2002[6]; Djordjevic et al, 2013[31]; Islam et al, 2013[59]; Ito et al, 2015[60]; Iwahashi et al, 2004[61]; Kwon et al, 2001[70]; Mahavorasirikul et al, 2009[79]; Nakajima et al, 2001[92], 2006[91]; Nurfadhlina et al, 2006[98]; Oscarson et al, 1999[102]; Peamkrasatam et al, 2006[107]; Takeshita et al, 2006[129]; Topcu et al, 2002[137]; Yoshida et al, 2002[150]). In the Middle East, the Turkish report a frequency of 23.9-69.7 % (Takeshita et al, 2006[129]; von Richter et al (2004[142]).…”

“…The American mestizo populations such as Brazilian and Ecuadorian show a frequency of 71.7 % (Rossini et al, 2006[115]) and 61.7 % (Soriano et al, 2011[124]), respectively. CYP2A6*1B frequency is higher in East and South Asian populations and is reported as 26.7-54.2 % (Ariyoshi et al, 2002[6]; Djordjevic et al, 2013[31]; Islam et al, 2013[59]; Ito et al, 2015[60]; Iwahashi et al, 2004[61]; Kwon et al, 2001[70]; Lourembam et al, 2015[77]; Mahavorasirikul et al, 2009[79]; Nakajima et al, 2001[92], 2006[91]; Nurfadhlina et al, 2006[98]; Oscarson et al, 1999[102]; Peamkrasatam et al, 2006[107]; Schoedel et al, 2004[117]; Takeshita et al, 2006[129]; Tiwawech et al, 2006[136]; Topcu et al, 2002[137]; Yoshida et al, 2002[150]; Yusof and Gan, 2009[152]). In Caucasians (Nonspecific, North American, Spanish, British, French, Swedish and Serbian) a frequency of 27.6-33.5 % (Bloom et al, 2011[17]; Djordjevic et al, 2013[31], 2010[30]; Gambier et al, 2005[42]; Haberl et al, 2005[46]; Huang et al, 2005[54]; Nakajima et al, 2006[91], 2004[95]; Oscarson et al, 1999[102]; Schoedel et al, 2004[117]; Soriano et al, 2011[124]) is reported, but it is lower in Turkish populations (25.9-26.7 % (Takeshita et al, 2006[129]; von Richter et al, 2004[142])).…”

“…East Asian populations such as Japanese (11.2-25.6 % (Ariyoshi et al, 2002[6]; Fujieda et al, 2004[36]; Fukami et al, 2006[39]; Ito et al, 2015[60]; Iwahashi et al, 2004[61]; Minematsu et al, 2003[85], 2006[84]; Nakajima et al, 2001[92], 2006[91]; Schoedel et al, 2004[117]; Takeshita et al, 2006[129]; Tamaki et al, 2011[130]; Xu et al, 2002[147]; Yoshida et al, 2002[150])), Chinese (4.9-14 % (Gu et al, 2005[44]; Liu et al, 2011[74]; Nurfadhlina et al, 2006[98]; Oscarson et al, 1999[102]; Schoedel et al, 2004[117]; Song et al, 2009[123]; Tan et al, 2001[131]; Xu et al, 2002[147]; Yuan et al, 2016[151])), Korean (9.4-11 %) (Djordjevic et al, 2013[31]; Fukami et al, 2006[39]; Kwon et al, 2001[70]; Nakajima et al, 2006[91]; Yoshida et al, 2002[150]), Thai (4-14.2 % (Mahavorasirikul et al, 2009[79]; Peamkrasatam et al, 2006[107]; Tiwawech et al, 2006[136])), Malaysian (7-16.7 % (Nurfadhlina et al, 2006[98]; Yusof and Gan, 2009[152])) and Vietnamese (11.8 % (Veiga et al, 2009[140])) showed the highest frequency among populations. However, some Asian populations that reside in a foreign country such as those living in the UK report a frequency of less than 1 % (Benowitz et al, 2006[13]; Huang et al, 2005[54]).…”

Methods for the quantitative evaluation and prediction of CYP enzyme induction using humanin vitrosystems

“…Artemisinin ü ü CYP2A6 Nicotine, coumarin [165] CYP2B6 Mephenytoin [166,167] CYP2C19 Omeprazole, mephenytoin [167,168] Bosentan ü CYP2C9 S-Warfarin [169] CYP3A4 Cyclosporine, glibenclamide, simvastatin [169] Carbamazepine ü ü CYP1A2 Caffeine [170] CYP2C9 Warfarin [171] CYP2B6 Bupropion [172] CYP3A4 Midazolam, alprazolam [173,174] Dexamethasone ü CYP3A4 Erythromycin [175] Efavirenz ü ü CYP3A4 Midazolam, atorvastatin [176] Indole-3-carbinol ü CYP1A2 Caffeine [177,178] Omeprazole ü CYP1A2 Caffeine [179,180] PAHs* ü CYP1A1 qPCR z [181] CYP1B1 qPCR z [182] Phenobarbital § ü ü CYP1A2 Theophylline [183] CYP2B6 Cyclophosphamide [184] CYP2C19 Hexobarbital [185] CYP3A4 Ethynylestradiol [186] Phenytoin ü ü CYP1A2 Theophylline [187] CYP2B6 Cyclophosphamide [188] CYP3A4 Lopinavir, midazolam [173,189] Rifampicin ü CYP1A2 Tizanidine, caffeine [190] CYP2B6 Bupropion [191] CYP2C8 Repaglinide, pioglitazone, rosiglitazone [192][193][194] CYP2C9 Warfarin, tolbutamide, glipizide [195,196] CYP2C19 Omeprazole [197] CYP3A4 Midazolam, nifedipine, repaglinide, zolpidem [6,[198][199][200] Ritonavir (with lopinavir) ü CYP1A2 Caffeine [201] CYP2B6 Buprop...…”