Metabolism of the antipsychotic drug olanzapine by CYP3A43

Zhao, Jie; Machalz, David; Liu, Sijie; Wolf, Clemens Alexander; Wolber, Gerhard; Parr, Maria Kristina; Bureik, Matthias

doi:10.1080/00498254.2022.2078751

Cited by 5 publications

(5 citation statements)

References 53 publications

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“…Due to the unavailability of a public crystal structure for CYP3A43, homology modeling based on the structurally most similar conformation of CYP3A4, which bears the highest amino acid sequence homology to CYP3A43 (identity: 75.7%, similarity: 86.7%), was performed. We conducted our previously [ 16 ] established workflow of rationalized template selection. The co-crystallized CYP3A4 ligand most similar to alprazolam was detected, and the corresponding crystal structure was, consequently, together with the UniProt [ 26 ] identifier (Q9HB55-1) for CYP3A43, chosen as input for the SWISSMODEL [ 27 ] server to generate the homology model.…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, there are comparatively few studies on this enzyme, and its crystal structure has not yet been resolved. There are reports on the differential effect of an intronic CYP3A43 polymorphism (rs472660) on olanzapine clearance in patients [ 14 , 15 ], and we were recently able to demonstrate by enzymatic assays that this antipsychotic is indeed a CYP3A43 substrate [ 16 ]. Another polymorphic gene variant (CYP3A43*3) contains the SNP rs680055 and codes for a mutated enzyme (CYP3A43:p.Pro340Ala), which is associated with an elevated risk for prostate cancer and also with increased mortality [ 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…Another polymorphic gene variant (CYP3A43*3) contains the SNP rs680055 and codes for a mutated enzyme (CYP3A43:p.Pro340Ala), which is associated with an elevated risk for prostate cancer and also with increased mortality [ 17 , 18 , 19 ]. CYP3A43:p.Leu293Pro and CYP3A43:p.Thr409Arg are two artificial mutants whose creation was inspired by the CYP3A4.18 and CYP3A7.2 alleles, respectively [ 20 ], and which influence the enzyme’s activity towards olanzapine [ 16 ]. Apart from olanzapine, the only known drug metabolized by CYP3A43 is alprazolam (see above).…”

Section: Introductionmentioning

confidence: 99%

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Changes in Alprazolam Metabolism by CYP3A43 Mutants

et al. 2022

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Alprazolam is a triazolobenzodiazepine which is most commonly used in the short-term management of anxiety disorders, often in combination with antipsychotics. The four human members of the CYP3A subfamily are mainly responsible for its metabolism, which yields the main metabolites 4-hydroxyalprazolam and α-hydroxyalprazolam. We performed a comparison of alprazolam metabolism by all four CYP3A enzymes upon recombinant expression in the fission yeast Schizosaccharomyces pombe. CYP3A4 and CYP3A5 show the highest 4-hydroxyalprazolam production rates, while CYP3A5 alone is the major producer of α-hydroxyalprazolam. For both metabolites, CYP3A7 and CYP3A43 show lower activities. Computational simulations rationalize the difference in preferred oxidation sites observed between the exemplary enzymes CYP3A5 and CYP3A43. Investigations of the alprazolam metabolites formed by three previously described CYP3A43 mutants (L293P, T409R, and P340A) unexpectedly revealed that they produce 4-hydroxy-, but not α-hydroxyalprazolam. Instead, they all also make a different metabolite, which is 5-N-O alprazolam. With respect to 4-hydroxyalprazolam, the mutants showed fourfold (T409R) to sixfold (L293P and P340A) higher production rates compared to the wild-type (CYP3A43.1). In the case of 5-N-O alprazolam, the production rates were similar for the three mutants, while no formation of this metabolite was found in the wild-type incubation.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Changes in Alprazolam Metabolism by CYP3A43 Mutants

et al. 2022

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“…CYP3A43 was found to participate in the biotransformation of endogenous testosterone and some drugs, including alprazolam and olanzapine. CYP3A43 is primarily expressed in the prostate but is also present at relatively low levels in the hepatic tissues compared to other CYP3 members [57]. The available data on CYP3A43 expression patterns in normal and cancerous ovary tissues are controversial.…”

Section: Cyp3a43mentioning

confidence: 99%

Targeting Cytochrome P450 Enzymes in Ovarian Cancers: New Approaches to Tumor-Selective Intervention

Al-saraireh,

Alshammari,

Abu-azzam

et al. 2023

Biomedicines

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Over the past decade, there have been significant developments in treatment for ovarian cancer, yet the lack of targeted therapy with few side effects still represents a major issue. The cytochrome P450 (CYP) enzyme family plays a vital role in the tumorigenesis process and metabolism of drugs and has a negative impact on therapy outcomes. Gaining more insight into CYP expression is crucial to understanding the pathophysiology of ovarian cancer since many isoforms are essential to the metabolism of xenobiotics and steroid hormones, which drive the disease’s development. To the best of our knowledge, no review articles have documented the intratumoral expression of CYPs and their implications in ovarian cancer. Therefore, the purpose of this review is to provide a clear understanding of differential CYP expression in ovarian cancer and its implications for the prognosis of ovarian cancer patients, together with the effects of CYP polymorphisms on chemotherapy metabolism. Finally, we discuss opportunities to exploit metabolic CYP expression for the development of novel therapeutic methods to treat ovarian cancer.

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“…CYP3A43 was found to participate in the biotransformation of endogenous testosterone and some drugs including alprazolam and olanzapine. CYP3A43 is primarily expressed in the prostate but is also present at relatively low levels in the hepatic tissues compared to other CYP3 members [37]. Available data on CYP3A43 expression patterns in normal and cancerous ovary tissues are controversial.…”

Section: Cyp3a43mentioning

confidence: 99%

Targeting Cytochrome P450 Enzymes in Ovarian Cancers: new approaches for Tumour-Selective Interventions

Al-saraireh,

Alshammari,

Abu-azzam

et al. 2023

Preprint

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Over the past decade, significant developments have occurred in treatment strategies for ovarian cancer, yet targeted therapy with few side effects is still a major issue. The cytochrome P450 (CYP) enzyme family plays a vital role in the tumorigenesis process and metabolism of drugs, with a negative impact on therapy outcomes. Gaining more insight into CYP expression is crucial for understanding the pathophysiology of ovarian cancer since many isoforms are essential for the metabolism of xenobiotics and steroid hormones, which drive the disease's development. The purpose of this review is to provide a clear understanding of differential CYP expression in ovarian cancer and its implications for the prognosis of ovarian cancer patients, together with their polymorphisms' effect on chemotherapy metabolism. Finally, we provide our thoughts on opportunities to exploit metabolic CYP expression for novel therapeutic development to treat ovarian cancer.

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Metabolism of the antipsychotic drug olanzapine by CYP3A43

Cited by 5 publications

References 53 publications

Changes in Alprazolam Metabolism by CYP3A43 Mutants

Changes in Alprazolam Metabolism by CYP3A43 Mutants

Targeting Cytochrome P450 Enzymes in Ovarian Cancers: New Approaches to Tumor-Selective Intervention

Targeting Cytochrome P450 Enzymes in Ovarian Cancers: new approaches for Tumour-Selective Interventions

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