Major Cytochrome P450 Enzymes Responsible for Microsomal Aldehyde Oxygenation of 11-Oxo-Δ8-tetrahydrocannabinol and 9-Anthraldehyde in Human Liver

Watanabe, Kazuhito; Matsunaga, Tamihide; Kimura, Toshiyuki; Funahashi, Tatsuya; Funae, Yoshihiko; Ohshima, Tohru; Yamamoto, Ikuo

doi:10.2133/dmpk.17.516

Cited by 6 publications

(10 citation statements)

References 23 publications

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“…In mammals, the oxidation of aromatic aldehydes, such as 11-oxo-Δ 8tetrahydrocannabinol, to its acid is primarily catalyzed in mice by hepatic P4502E1 [37]. Also, hepatic microsomes from various animals possess the ability to oxidize xenobiotic aldehydes to carboxylic acids (Figure 1) by the P450 system [27]. More recently, model substrates, 9-AA and 4-biphenylaldehyde, have been used to measure the activity of several P450s [28,29].…”

Section: Discussionmentioning

confidence: 99%

“…The oxidation of anthracene-9-carboxaldehyde (9-AA) by P450 enzymes (Figure 1) was determined by measuring the formation of anthracene-9-carboxylic acid (9-ACA) as described by Watanabe et al [27] and Marini et al [28]. In brief, the incubation mixture included recombinant P450s (50 nM) or mouse liver microsomes (0.25 mg/mL, ∼50 nM P450), an NADPH-regenerating system consisting of 0.25 mM NADPH, 4.25 mM isocitric acid, 50 mM MgCl 2 , and 1.3 Units/mL isocitrate dehydrogenase, 0.025 mM 9-AA, and 0.1 M potassium phosphate buffer, pH 7.4.…”

Section: Anthracene-9-carboxaldehyde Oxidation Assaymentioning

confidence: 99%

“…Watanabe et al [31] showed that P4502c29 is an aldehyde oxygenase utilizing a cannabinoid aldehyde at low μM concentrations as a substrate. Therefore, we sought to evaluate the ability of a number of P450s for their ability to oxidize a synthetic aldehyde substrate, 9-AA [27,28]. Several P450s rapidly metabolized the aldehyde compound, while others apparently did not oxidize this aldehyde to its carboxylic acid (Table 1).…”

Section: Evaluation Of P450s Capable Of Catalyzing Anthracene-9-carbomentioning

confidence: 99%

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Cytochromes P450 catalyze oxidation of α,β-unsaturated aldehydes

Amunom

Stephens

Tamási

et al. 2007

Archives of Biochemistry and Biophysics

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We sought to establish whether heme-thiolate monooxygenases oxidize, alpha,beta-unsaturated aldehydes generated during lipid peroxidation. Several recombinant P450s co-expressed with NADPH:P450 oxidoreductase were surveyed for aldehyde oxidation activity with anthracene-9-carboxaldehyde and 4-hydroxy-trans-2-nonenal (HNE). Murine P4502c29, human P4503A4, human P4502B6, and rabbit P4502B4 were good catalysts of aldehyde oxidation to carboxylic acids. Other P450s (e.g., P4501A2, 2E1, and 2J2) did not oxidize these aldehydes. P4502c29 and P4503A4 displayed K(m)/S(0.5) values of approx. 1-20microM. The product measured by HPLC that co-migrates with authentic 4-hydroxynonenoic acid (HNA) had a mass spectrum identical to the standard. Using P4502c29, HNE was a mixed-competitive inhibitor of anthracene-9-carboxaldehyde oxidation, suggesting that both aldehydes are substrates for P4502c29. Specific inhibitors of aldehyde dehydrogenases and P450 were used to assess their role in the metabolism of HNE in primary rat hepatocytes. Inhibitors of aldehyde dehydrogenase (cyanamide) inhibited HNA formation by 60% and together cyanamide and miconazole (P450) caused over 85% inhibition of HNA formation. P450s are significant participants in metabolism of endogenous and exogenous unsaturated aldehydes in primary rat hepatocytes.

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Section: Discussionmentioning

confidence: 99%

Section: Anthracene-9-carboxaldehyde Oxidation Assaymentioning

confidence: 99%

Section: Evaluation Of P450s Capable Of Catalyzing Anthracene-9-carbomentioning

confidence: 99%

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Cytochromes P450 catalyze oxidation of α,β-unsaturated aldehydes

Amunom

Stephens

Tamási

et al. 2007

Archives of Biochemistry and Biophysics

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“…Based on studies to date, (CYP-450) 2C9 and 3A4 are predicted to play major roles in the primary metabolism of THC. (Bland et al, 2005;Bornheim et al, 1992;Richardson et al, 1995;Watanabe et al, 1995;Watanabe et al, 2007) Secondary THC metabolism may occur via several pathways: 7-OH Δ 8 -THC by CYP-450 isoforms (primarily 3A4); (Matsunaga et al, 2000) 11-OH-Δ 9 -THC and 11-nor-9-carboxy-Δ 9 -THC (THC-COOH) by several UGT isoforms; (Mazur et al, 2009) 11-oxo-Δ 8 -THC by CYP-450 isoforms (primarily 2C9); (Watanabe et al, 2002) and some epoxide metabolites of Δ 8 -THC by epoxide hydrolase. (Yamamoto et al, 1984) THC metabolic findings are generally consistent across overlapping studies, despite variability in the specific form of THC used (Δ 8 , Δ 9 , or plant-extracted mixed isomers).…”

Section: In Vitro and Ex Vivo Datamentioning

confidence: 99%

“…Caption: Supporting data: (Bland et al, 2005;Bornheim et al, 1992;Chimalakonda et al, 2012;Jiang et al, 2011;Matsunaga et al, 2000;Richardson et al, 1995;Watanabe et al, 2002;Watanabe et al, 1995;Watanabe et al, 2007) CYP-450 isoform 1A1 1A2 2A6 2B6 2C8 2C9 2C18 2C19 2D6 2E1 3A4 3A5 4A11 Δ 9 -THC * * Potential substrate CBD * * Low or not significant CBN * * Not studied Δ 8 -THC * * * Highest predicted 7-OH-Δ 8 -THC * significance in vivo 11-oxo-Δ 8 -THC * JWH-018 * * AM2201 * *…”

Section: Figurementioning

confidence: 99%

Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review

Stout¹,

Cimino²

2013

Drug Metabolism Reviews

300

230

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Exogenous cannabinoids are structurally and pharmacologically diverse compounds that are widely used. The purpose of this systematic review is to summarize the data characterizing the potential for these compounds to act as substrates, inhibitors, or inducers of human drug metabolizing enzymes, with the aim of clarifying the significance of these properties in clinical care and drug interactions. In vitro data were identified that characterize cytochrome P-450 (CYP-450) enzymes as potential significant contributors to the primary metabolism of several exogenous cannabinoids: tetrahydrocannabinol (THC; CYPs 2C9, 3A4); cannabidiol (CBD; CYPs 2C19, 3A4); cannabinol (CBN; CYPs 2C9, 3A4); JWH-018 (CYPs 1A2, 2C9); and AM2201 (CYPs 1A2, 2C9). CYP-450 enzymes may also contribute to the secondary metabolism of THC, and UDP-glucuronosyltransferases have been identified as capable of catalyzing both primary (CBD, CBN) and secondary (THC, JWH-018, JWH-073) cannabinoid metabolism. Clinical pharmacogenetic data further support CYP2C9 as a significant contributor to THC metabolism, and a pharmacokinetic interaction study using ketoconazole with oromucosal cannabis extract further supports CYP3A4 as a significant metabolic pathway for THC and CBD. However, the absence of interaction between CBD from oromucosal cannabis extract with omeprazole suggests a less significant role of CYP2C19 in CBD metabolism. Studies of THC, CBD, and CBN inhibition and induction of major human CYP-450 isoforms generally reflect a low risk of clinically significant drug interactions with most use, but specific human data are lacking. Smoked cannabis herb (marijuana) likely induces CYP1A2 mediated theophylline metabolism, although the role of cannabinoids specifically in eliciting this effect is questionable.

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Hexahydrocannabinol and closely related semi‐synthetic cannabinoids: A comprehensive review

Ujváry¹

2023

Drug Testing and Analysis

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Since the early 2000s, there has been a turmoil on the global illicit cannabinoid market. Parallel to legislative changes in some jurisdictions regarding herbal cannabis, unregulated and cheap synthetic cannabinoids with astonishing structural diversity have emerged. Recently, semi‐synthetic cannabinoids manufactured from hemp extracts by simple chemical transformations have also appeared as recreational drugs. The burst of these semi‐synthetic cannabinoids into the market was sparked by legislative changes in the United States, where cultivation of industrial hemp restarted. By now, hemp‐derived cannabidiol (CBD), initially a blockbuster product on its own, became a “precursor” to semi‐synthetic cannabinoids such as hexahydrocannabinol (HHC), which appeared on the drug market in 2021. The synthesis and cannabimimetic activity of HHC were first reported eight decades ago in quest for the psychoactive principles of marijuana and hashish. Current large‐scale manufacture of HHC is based on hemp‐derived CBD extract, which is converted first by cyclization into a Δ8/Δ9‐THC mixture, followed by catalytic hydrogenation to afford a mixture of (9R)‐HHC and (9S)‐HHC epimers. Preclinical studies indicate that (9R)‐HHC has THC‐like pharmacological properties. The animal metabolism of HHC is partially clarified. The human pharmacology including metabolism of HHC is yet to be investigated, and (immuno)analytical methods for the rapid detection of HHC or its metabolites in urine are lacking. Herein, the legal background for the revitalization of hemp cultivation, and available information on the chemistry, analysis, and pharmacology of HHC and related analogs, including HHC acetate (HHC‐O) is reviewed.

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Major Cytochrome P450 Enzymes Responsible for Microsomal Aldehyde Oxygenation of 11-Oxo-Δ8-tetrahydrocannabinol and 9-Anthraldehyde in Human Liver

Cited by 6 publications

References 23 publications

Cytochromes P450 catalyze oxidation of α,β-unsaturated aldehydes

Cytochromes P450 catalyze oxidation of α,β-unsaturated aldehydes

Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review

Hexahydrocannabinol and closely related semi‐synthetic cannabinoids: A comprehensive review

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