Pinoline may be used as a probe for CYP2D6 activity

Xi Ling Jiang, Hong Wu Shen, Aiming Yu

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Pinoline, 6-methoxy-1,2,3,4-tetrahydro-β-carboline, is a serotonin analog that selectively inhibits the activity of monoamine oxidase-A and shows antidepressant activity. Our previous study using a panel of recombinant cytochrome P450 (P450) enzymes suggests that pinoline O-demethylation may be selectively catalyzed by polymorphic CYP2D6. The current study, therefore, aimed to delineate the impact of CYP2D6 status on pinoline metabolism. Enzyme kinetic studies using recombinant CYP2D6 allelic isozymes revealed that CYP2D6.2 exhibited 5-fold lower enzyme efficiency (V max/K m) toward pinoline compared with CYP2D6.1, and CYP2D6.10 did not show any catalytic activity. Inhibition study showed that quinidine (1 μM) completely blocked pinoline O-demethylase activity in human liver microsomes, whereas other P450 isoform-selective inhibitors had no or minimal effects. Pinoline O-demethylase activities in 10 human liver microsomes showed significantly strong correlation with bufuralol 1′-hydroxylase activities (R 2 = 0.93; p < 0.0001) and CYP2D6 contents (R 2 = 0.82; p = 0.005), whereas no appreciable correlations with enzymatic activities of other P450 enzymes were found. Furthermore, we compared pinoline urinary metabolic ratio (pinoline/6-hydroxy-1,2,3,4-tetrahydro-β-carboline) between CVP2D6-humanized and wild-type control mice after intraperitoneal injection of pinoline (30 mg/kg). Results indicated that the two genotyped mice were clearly distinguished by pinoline metabolic ratio (mean ± S.D.), which was much higher in wild-type mice (0.29 ± 0.19, n = 4) than in CVP2D6-humanized transgenic mice (0.0070 ± 0.0048, n = 4). Our findings suggest that pinoline O-demethylation is governed by CYP2D6 status, and pinoline, at a proper concentration or dose, may be a good probe to evaluate CYP2D6 activity.

Original languageEnglish (US)
Pages (from-to)443-446
Number of pages4
JournalDrug Metabolism and Disposition
Issue number3
StatePublished - Mar 2009
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science


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