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Biochemical Pharmacology (v.82, #7)

Editorial Advisory Board (pp. iii).

Role of DNA damage in atherosclerosis—Bystander or participant? by Kelly Gray; Martin Bennett (pp. 693-700).

Atherosclerosis leading to cardiovascular disease is the leading cause of death among western populations. Atherosclerosis in characterised by the development of a fibrofatty lesion that consists of a diverse cell population, including inflammatory cells that create an intensely oxidising environment within the vessel. Coupled with normal replication, the local intracellular and extracellular environment causes damage to cellular DNA that is recognised and repaired by the DNA damage response (DDR) pathway. The role of DNA damage and the resulting deregulation of ‘normal’ cellular behaviour and subsequent loss of cell cycle control checkpoints have been widely studied in cancer. However, despite the extensive evidence for DNA damage in atherosclerosis, it is only over the past two decades that a causative link between DNA damage and atherosclerosis has been hypothesised. Whilst atherosclerosis is a feature of human disease characterised by defects in DNA damage, currently the role of DNA damage in the initiation and progression of atherosclerosis remains highly debated, as a ‘chicken and egg’ situation. This review will analyse the evidence for, the causes of, and consequences of DNA damage in atherosclerosis, detail the DNA damage response pathway that results in these consequences, and highlight therapeutic opportunities in this area. We also outline the evidence that DNA damage is a cause of both initiation and progression of atherosclerosis, and not just a consequence of disease.

Keywords: Abbreviations; ApoE; ^−/−; Apolipoprotein E deficient; ATM; Ataxia Telangiectasia Mutated; ATR; ATM- and Rad3-related protein; BER; base-excision repair; CHK1/2; checkpoint kinase 1 or checkpoint kinase 2; CtIP; C-terminal interacting protein; DDR; DNA damage response pathway; DSB; double strand break; γ-H2AX; gamma-phosphorylated form of histone 2A protein; HGPS; Hutchinson–Gilford Progeria Syndrome; HR; homologous recombination; ICAM-1; inter-cellular adhesion molecule 1; LDL; low-density lipoprotein; IL-6/8; interleukin-6/8; iNOS; inducible nitric oxide synthase; IR; ionising radiation; MDC1; mediator of DNA damage checkpoint protein 1; MRN; Complex of Nibrin (NBS-1) MRE11 and Rad50; MtDNA; mitochondrial DNA; NBS-1; Nijmegen Breakage Syndrome 1 or Nibrin; NER; nucleotide excision repair; NHEJ; non-homologous end joining; ROS; reactive oxygen species; SIPS; stress induced premature senescence; SMC; structural maintenance of chromosomes; SSBs; single strand breaks; UV; ultra violet; VSMCs; vascular smooth muscle cellsAtherosclerosis; DNA damage; Apoptosis; Senescence

Occurrence, function and potential medicinal applications of the phytohormone abscisic acid in animals and humans by Hai-Hang Li; Rui-Lin Hao; Shan-Shan Wu; Peng-Cheng Guo; Chang-Jian Chen; Li-Ping Pan; He Ni (pp. 701-712).

Abscisic acid (ABA) is an important phytohormone that regulates plant growth, development, dormancy and stress responses. Recently, it was discovered that ABA is produced by a wide range of animals including sponges ( Axinella polypoides), hydroids ( Eudendrium racemosum), human parasites ( Toxoplasma gondii), and by various mammalian tissues and cells (leukocytes, pancreatic cells, and mesenchymal stem cells). ABA is a universal signaling molecule that stimulates diverse functions in animals through a signaling pathway that is remarkably similar to that used by plants; this pathway involves the sequential binding of ABA to a membrane receptor and the activation of ADP-ribose cyclase, which results in the overproduction of the intracellular cyclic ADP-ribose and an increase in intracellular Ca²⁺ concentrations. ABA stimulates the stress response (heat and light) in animal cells, immune responses in leukocytes, insulin release from pancreatic β cells, and the expansion of mesenchymal and colon stem cells. ABA also inhibits the growth and induces the differentiation of cancer cells. Unlike some drugs that act as cell killers, ABA, when functioning as a growth regulator, does not have significant toxic side effects on animal cells. Research indicated that ABA is an endogenous immune regulator in animals and has potential medicinal applications for several human diseases. This article summarizes recent advances involving the discovery, signaling pathways and functions of ABA in animals.

Keywords: Abscisic acid; Animals; Humans; Pharmacological function; Signaling pathway

Cyanidin-3-O-β-glucoside with the aid of its metabolite protocatechuic acid, reduces monocyte infiltration in apolipoprotein E-deficient mice by Dongliang Wang; Tangbin Zou; Yan Yang; Xiao Yan; Wenhua Ling (pp. 713-719).

Polyphenols, including anthocyanins, from various plant foods are effective in reducing the severity of atherosclerosis in animal and human studies. Due to the poor understanding of the bioavailability of anthocyanins, the potential antiatherogenic mechanisms underlying the action remain largely unknown. Herein, we found that oral gavage of cyanidin-3-O-β-glucoside (Cy-3-G) could be transformed into protocatechuic acid (PCA), and the plasma maximal levels of Cy-3-G were 3.7-fold lower than that of PCA in the apolipoprotein E (ApoE)-deficient mice. Subsequently, we observed that PCA treatment has a higher capacity than Cy-3-G treatment in decreasing CC chemokine receptor 2 (CCR2) expression in the mouse peripheral blood monocytes (PBMs), along with reducing the mouse PBMs chemokine toward CC ligand-2 (CCL2) in a Boyden chamber. Interesting, in the ApoE-deficient mouse model, orally gavaged with Cy-3-G has a higher ability than gavaged with PCA to reduce CCR2 expression in PBMs. PBMs deprived from the Cy-3-G-treated ApoE-deficient mice have a lower ability than those from PCA-treated animals to migrate toward CCL2. Furthermore, as compared with the PCA group, Cy-3-G treatment more efficiently reduced thioglycollate-induced macrophage infiltration into the abdominal cavity. Thus, we suggest that Cy-3-G may reduce the monocyte infiltration in mice via down-regulation of CCR2 expression in monocytes, at least in part, with the aid of its metabolite PCA. These above data imply that the anti-monocyte/macrophage infiltration property of Cy-3-G and its metabolite PCA may be an important antiatherogenic mechanism for anthocyanins.

Keywords: Anthocyanins; Protocatechuic acid; Chemokine receptor; Monocyte; Atherosclerosis

Protein kinase Cδ mediates the activation of protein kinase D2 in platelets by Dheeraj Bhavanasi; Soochong Kim; Lawrence E. Goldfinger; Satya P. Kunapuli (pp. 720-727).

Protein kinase D (PKD) is a subfamily of serine/threonine specific family of kinases, comprised of PKD1, PKD2 and PKD3 (PKCμ, PKD2 and PKC v in humans). It is known that PKCs activate PKD, but the relative expression of isoforms of PKD or the specific PKC isoform/s responsible for its activation in platelets is not known. This study is aimed at investigating the pathway involved in activation of PKD in platelets. We show that PKD2 is the major isoform of PKD that is expressed in human as well as murine platelets but not PKD1 or PKD3. PKD2 activation induced by AYPGKF was abolished with a G_q inhibitor YM-254890, but was not affected by Y-27632, a RhoA/p160ROCK inhibitor, indicating that PKD2 activation is G_q-, but not G_12/13-mediated Rho-kinase dependent. Calcium-mediated signals are also required for activation of PKD2 as dimethyl BAPTA inhibited its phosphorylation. GF109203X, a pan PKC inhibitor abolished PKD2 phosphorylation but Go6976, a classical PKC inhibitor had no effect suggesting that novel PKC isoforms are involved in PKD2 activation. Importantly, Rottlerin, a non-selective PKCδ inhibitor, inhibited AYPGKF-induced PKD2 activation in human platelets. Similarly, AYPGKF- and Convulxin-induced PKD2 phosphorylation was dramatically inhibited in PKCδ-deficient platelets, but not in PKCθ- or PKCɛ-deficient murine platelets compared to that of wild type platelets. Hence, we conclude that PKD2 is a common signaling target downstream of various agonist receptors in platelets and G_q-mediated signals along with calcium and novel PKC isoforms, in particular, PKCδ activate PKD2 in platelets.

Keywords: Abbreviations; ADP; adenosine diphosphate; PKC; protein kinase C; PKD2; protein kinase D; PAR-4; protease activated receptor-4; P2Y; ₁₂; platelet ADP receptor coupled to inhibition of adenylyl cyclase; DAG; diacyl glycerol; MARCKS; myristoylated alanine-rich C-kinase substrate; CDCrel1; cell division cycle related-1; PI 3-kinase; phosphoinositide 3-kinase; SFK; Src family kinases; GPVI; glycoprotein; PIP2; phosphotidylinositol 4,5-bisphosphate; BAPTA; 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acidProtein kinase C; Calcium; Protein kinase D; Protease activated receptor; Platelet; G; _q

Stimulation of gastric ulcer healing by heat shock protein 70 by Tomoaki Ishihara; Shintaro Suemasu; Teita Asano; Ken-ichiro Tanaka; Tohru Mizushima (pp. 728-736).

It is important in treatment of gastric ulcers to not only prevent further ulcer formation but also enhance ulcer healing. When cells are exposed to gastric irritants, expression of heat shock proteins (HSPs) is induced, making the cells resistant to the irritants. We recently reported direct evidence that HSPs, especially HSP70, are preventive against irritant-induced gastric ulcer formation. Gastric ulcer healing is a process involving cell proliferation and migration at the gastric ulcer margin and angiogenesis in granulation tissue. In this study, we have examined the role of HSP70 in gastric ulcer healing. Gastric ulcers were produced by focal and serosal application of acetic acid. Expression of HSP70 was induced in both the gastric ulcer margin and granulation tissue. Compared with wild-type mice, gastric ulcer healing was accelerated in transgenic mice expressing HSP70, and both cell proliferation at the gastric ulcer margin and angiogenesis in granulation tissue were enhanced. Oral administration of geranylgeranylacetone, an inducer of HSPs, to wild-type mice, either prior to or after ulcer formation, not only induced expression of HSP70 in the stomach but also accelerated gastric ulcer healing. On the other hand, oral administration of purified recombinant HSP70 prior to the ulcer formation, but not after formation, stimulated gastric ulcer healing. This study provides the first evidence that HSP70 accelerates gastric ulcer healing. The results also suggest that both the HSP70 produced prior to ulcer formation and released from damaged cells, and the HSP70 produced after ulcer formation are involved in this accelerated healing process.

Keywords: Abbreviations; NSAIDs; non-steroidal anti-inflammatory drugs; PGs; prostaglandins; HSPs; heat shock proteins; HSF1; heat shock factor 1; GGA; geranylgeranylacetone; bFGF; basic fibroblast growth factor; IGF; insulin-like growth factor; TGF; transforming growth factor; VEGF; vascular endothelial growth factor; BrdU; 5-bromo-2′-deoxyuridine; EIA; enzyme immuno assay; ELISA; enzyme-linked immunosorbent assay; GAPDH; glyceraldehyde-3-phosphate dehydrogenase; DAMP; damage-associated molecular patternsUlcer healing; Heat shock protein 70; Geranylgeranylacetone; Proliferation; Angiogenesis

Protective effect of ellagic acid, a natural polyphenolic compound, in a murine model of Crohn's disease by M.A. Rosillo; M. Sanchez-Hidalgo; A. Cárdeno; C. Alarcón de la Lastra (pp. 737-745).

Current epidemiological and experimental studies support a beneficial role of dietary polyphenols in several gastrointestinal diseases, including inflammatory bowel disease. The aim of this study was to gain a better understanding of the effects of a naturally occurring polyphenol, ellagic acid, present in some fruits such as pomegranate, raspberries and nuts among others, in an experimental murine model of Crohn's disease by intra-colonic administration of TNBS in rats. Analysis of the lesions were carried out by macroscopic and histological technics. Inflammation response was assessed by histology and myeloperoxidase activity. iNOS and COX-2 are upregulated by MAPKs and NF-κB nuclear transcription factor in intestinal epithelial cells thus, we determined the expression of iNOS, COX-2 and the involvement of the p38, JNK, ERK1/2 MAPKs and NF-κB signalling in the protective effect of EA by western blotting. Oral administration of EA (10–20mg/kg) diminished the severity and extension of the intestinal injuries induced by TNBS although there was no observed a significant dose–response. In addition, EA increased mucus production in goblet cells in colon mucosa, decreased neutrophil infiltration and pro-inflammatory proteins COX-2 and iNOS overexpression. Also EA was capable of reducing the activation of p38, JNK and ERK1/2 MAPKs, preventing the inhibitory protein IκB-degradation and inducing an inhibition of the nuclear translocation level of p65 in colonic mucosa. In conclusion, EA reduces the damage in a rat model of Crohn's disease, alleviates the oxidative events and returns pro-inflammatory proteins expression to basal levels probably through MAPKs and NF-κB signalling pathways.

Keywords: Ellagic acid; TNBS; Oxidative stress; COX-2; MAPK; NF-κB

Pharmacological profile of FK881(ASP6537), a novel potent and selective cyclooxygenase-1 inhibitor by Junko Imanishi; Yoshiaki Morita; Eiji Yoshimi; Kanae Kuroda; Tomoko Masunaga; Kaoru Yamagami; Masako Kuno; Emi Hamachi; Satoshi Aoki; Fumie Takahashi; Katsuya Nakamura; Susumu Miyata; Yoshitaka Ohkubo; Seitaro Mutoh (pp. 746-754).

Nonsteroidal anti-inflammatory drugs (NSAIDs) are now understood to fall into one of two agent classes in clinical use. Traditional NSAIDs inhibit both cyclooxygenases-1 and 2 (COX-1, 2), which act as key enzymes catalyzing the same reaction in the production of prostaglandins (PGs), while the second class of NSAIDs selectively inhibit COX-2. Inhibition of the inducible COX-2 isoform is believed to be responsible for the therapeutic effects of NSAIDs, such as anti-inflammatory, analgesic, and antipyretic effects, while COX-1 inhibition results in side-effects on the gastrointestinal (GI) system. In the present study, however, we changed this notion that inhibiting only COX-1 causes adverse effects. We discovered FK881, a specific COX-1 inhibitor which exhibits a 650-fold ratio for human whole blood COX-1/COX-2 and rats in vivo. In rats, FK881 dose dependently inhibited carrageenan-induced paw edema (ED30: 22mg/kg; diclofenac ED30: 3.6mg/kg, rofecoxib ED30: 26mg/kg) and paw swelling associated with adjuvant arthritis (ED50: 17mg/kg; diclofenac ED50: 1.4mg/kg, rofecoxib ED50: 1.8mg/kg). Further, FK881 dose dependently inhibited acetic acid-induced writhing in mice (ED50: 19mg/kg; diclofenac ED50: 14mg/kg, rofecoxib ED50: >100mg/kg) and adjuvant arthritis hyperalgesia in rats (ED50: 1.8mg/kg; diclofenac ED50: 1.0mg/kg, rofecoxib ED50: 0.8mg/kg). However, unlike traditional NSAIDs, GI tolerability was improved, although the antipyretic effect of FK881 was weak (NOEL: >320mg/kg; diclofenac NOEL: <1mg/kg, rofecoxib NOEL: 100mg/kg). These results suggest that FK881 may be useful in treating symptoms of rheumatoid arthritis and osteoarthritis.

Keywords: Cyclooxygenases-1; Inhibitor; NSAIDs; Gastrointestinal toxicity; Hyperalgesia; Inflammation

Discovery of a novel COX-2 inhibitor as an orally potent anti-pyretic and anti-inflammatory drug: Design, synthesis, and structure–activity relationship by Shigeo Hayashi; Yoko Sumi; Naomi Ueno; Akio Murase; Junji Takada (pp. 755-768).

Cyclooxygenase (COX) has been considered as a significant pharmacological target because of its pivotal roles in the prostaglandin biosynthesis and following cascades that lead to various (patho)physiological effects. Non-steroidal anti-inflammatory drugs (NSAIDs) that suppress COX activities have been used clinically for the treatment of fever, inflammation, and pain; however, nonselective COX inhibitors exhibit serious side-effects such as gastrointestinal damage because of their inhibitory activities against COX-1. Thus, COX-1 is constitutive and expressed ubiquitously and serves a housekeeping role, while COX-2 is inducible or upregulated by inflammatory/injury stimuli such as interleukin-1β, tumor necrosis factor-α, and lipopolysaccharide in macrophage, monocyte, synovial, liver, and lung, and is associated with prostaglandin E₂ and prostacyclin production that evokes or sustains systemic/peripheral inflammatory symptoms. Also, hypersensitivity of aspirin is a significant concern clinically. Hence, design, synthesis, and structure–activity relationship of [2-{[(4-substituted)-pyridin-2-yl]carbonyl}-(6- or 5-substituted)-1 H-indol-3-yl]acetic acid analogues were investigated to discover novel acid-type COX-2 inhibitor as an orally potent new-class anti-pyretic and anti-inflammatory drug. As significant findings, compounds1–3 demonstrated potent COX-2 inhibitory activities with high selectivities for COX-2 over COX-1 in human cells or whole-blood in vitro, and demonstrated orally potent anti-pyretic activity against lipopolysaccharide-induced systemic-inflammatory fever model in F344 rats. Also compound1 demonstrated orally potent anti-inflammatory activity against edema formation and a suppressive effect against PGE₂ production in carrageenan-induced peripheral-inflammation model on the paw of SD rats. These results suggest that compounds1–3 are potential agents for the treatment of inflammatory disease and are useful for further pharmacological COX-2 inhibitor investigations.

Keywords: Abbreviations; COX; cyclooxygenase (or endoperoxidase, or prostaglandin G/H synthase, EC 1.14.99.1); AA; arachidonic acid; PG; prostaglandin; PGH; ₂; prostaglandin H; ₂; PGG; ₂; prostaglandin G; ₂; PGE; ₂; prostaglandin E; ₂; PGI; ₂; prostacyclin; 6-keto-PGF; _1α; 6-keto-prostaglandin F; ₁; α; TXA; ₂; thromboxane A; ₂; TXB; ₂; thromboxane B; ₂; NSAID; non-steroidal anti-inflammatory drug; SPF; specific pathogen free; VAF; virus antibody free; F344 rat; Fischer 344 rat; SD rat; Sprague–Dawley rat; TNF-α; tumor necrosis factor-α; IL-1β; interleukin-1β; IL-6β; interleukin-6β; DBU; 1,8-diazabicyclo[5.4.0]undec-7-ene; LPS; lipopolysaccharide; HUVEC; human umbilical vein endothelial cell; HWP; human washed platelet; RA; rheumatoid arthritis; OA; osteoarthritis; HBD; hydrogen bond donor; HBA; hydrogen bond acceptorNSAID; COX-2/COX-1 selectivity; Orally active COX-2 inhibitor; LPS-induced fever; Carrageenan-induced edema; Inflammation

β₁-Adrenergic receptor-mediated HO-1 induction, via PI3K and p38 MAPK, by isoproterenol in RAW 264.7 cells leads to inhibition of HMGB1 release in LPS-activated RAW 264.7 cells and increases in survival rate of CLP-induced septic mice by Yu Mi Ha; Sun Ah Ham; Young Min Kim; Young Soo Lee; Hye Jung Kim; Han Geuk Seo; Jae Heun Lee; Min Kyu Park; Ki Churl Chang (pp. 769-777).

High mobility group box (HMGB)-1 plays an important role in sepsis-associated death in experimental studies. Heme oxygenase-1 (HO-1) inducers were reported to reduce HMGB1 release in experimental sepsis. Previously, we reported on the importance of the β1-adrenergic receptor and protein kinase A pathway in the regulation of HO-1 expression by isoproterenol (ISO) in RAW 264.7 cells. We investigated whether ISO reduces HMGB1 release in LPS-activated RAW 264.7 cells and improves survival rate in septic mice due to HO-1 induction. ISO concentration-dependently increased HO-1 via Nrf-2 translocation and inhibited release of HMGB1 through the β₁-adrenergic receptor (β₁-AR) in LPS-activated RAW 264.7 cells. This conclusion was supported by the finding that dobutamine but not salbutamol increased HO-1 expression in both RAW 264.7 cells. ISO failed to inhibit HMGB1 release when HO-1 expression was suppressed by ZnPPIX, an HO-1 inhibitor in RAW 264.7 cells. ISO significantly inhibited phosphorylation of IκB-α and NF-κB-driven luciferase activity in LPS-activated RAW 264.7 cells. In addition, LY294002, a PI3K inhibitor, and SB203580, a p38 MAPK inhibitor, significantly inhibited not only HO-1 induction but also HMGB1 release by ISO. Importantly, ISO increased HO-1 protein expression in heart and lung tissues, reduced HMGB1 in plasma and increased survival rate in CLP-treated septic mice, which was significantly reversed by co-treatment with ZnPPIX. Taken together, we conclude that inhibition of HMGB1 release during sepsis via β₁-AR-mediated HO-1 induction is a novel mechanism for the beneficial effects of ISO in the treatment of sepsis.

Keywords: Abbreviations; β-AR; beta adrenergic receptor; CLP; cecal ligation and puncture; CO; carbon monoxide; HMGB1; high mobility group box 1; HO-1; heme oxygenase-1; ISO; isoproterenol; LPS; lipopolysaccharides; MAPK; mitogen-activated protein kinase; Nrf2; nuclear factor-erythroid 2-related factor 2; PI3K; phosphoinositol-3-kinaseHeme oxygenase-1; Sepsis; Isoproterenol; β; ₁; -Adrenergic receptor; Mice

Interplay between Ret and Fap-1 regulates CD95-mediated apoptosis in medullary thyroid cancer cells by Valentina Nicolini; Giuliana Cassinelli; Giuditta Cuccuru; Italia Bongarzone; Giovanna Petrangolini; Monica Tortoreto; Piera Mondellini; Patrizia Casalini; Enrica Favini; Nadia Zaffaroni; Franco Zunino; Cinzia Lanzi (pp. 778-788).

Emerging evidence suggests that Ret oncoproteins expressed in medullary thyroid cancer (MTC) might evade the pro-apoptotic function of the dependence receptor proto-Ret by directly impacting the apoptosis machinery. Identification of the molecular determinants of the interplay between Ret signaling and apoptosis might provide a relevant contribution to the optimization of Ret-targeted therapies. Here, we describe the cross-talk between Ret-M918T oncogenic mutant responsible for type 2B multiple endocrine syndrome (MEN2B), and components of death receptor-mediated extrinsic apoptosis pathway. In the human MEN2B-type MTC cell line MZ-CRC-1 expressing Ret-M918T, Ret was found associated with Fap-1, known as inhibitor of the CD95 death receptor trafficking to the cell membrane, and with procaspase-8, the initiator pro-form caspase in the extrinsic apoptosis pathway. Cell treatment with the anti-tumor Ret kinase inhibitor RPI-1 inhibited tyrosine phosphorylation of procaspase-8, likely inducing its local activation, followed by downregulation of both Ret and Fap-1, and translocation of CD95 into lipid rafts. According to the resulting increase of CD95 cell surface expression, the CD95 agonist antibody CH11 enhanced RPI-1-induced cell growth inhibition and apoptosis. RET RNA interference downregulated Fap-1 protein in MZ-CRC-1 cells, whereas exogenous RET-M918T upregulated Fap-1 in HEK293 cells. Overall, these data indicate that the Ret oncoprotein exerts opposing controls on Fap-1 and CD95, increasing Fap-1 expression and decreasing CD95 cell surface expression. The functional interplay of the Ret mutant with the extrinsic apoptosis pathway provides a mechanism possibly contributing to MTC malignant phenotype and a rational basis for novel therapeutic strategies combining Ret inhibitors and CD95 agonists.

Keywords: RET oncogene; Medullary thyroid cancer; Fap-1; CD95; MEN2B; Caspase 8

Preparation of human drug metabolites using fungal peroxygenases by Marzena Poraj-Kobielska; Matthias Kinne; René Ullrich; Katrin Scheibner; Gernot Kayser; Kenneth E. Hammel; Martin Hofrichter (pp. 789-796).

The synthesis of hydroxylated and O- or N-dealkylated human drug metabolites (HDMs) via selective monooxygenation remains a challenging task for synthetic organic chemists. Here we report that aromatic peroxygenases (APOs; EC 1.11.2.1) secreted by the agaric fungi Agrocybe aegerita and Coprinellus radians catalyzed the H₂O₂-dependent selective monooxygenation of diverse drugs, including acetanilide, dextrorphan, ibuprofen, naproxen, phenacetin, sildenafil and tolbutamide. Reactions included the hydroxylation of aromatic rings and aliphatic side chains, as well as O- and N-dealkylations and exhibited different regioselectivities depending on the particular APO used. At best, desired HDMs were obtained in yields greater than 80% and with isomeric purities up to 99%. Oxidations of tolbutamide, acetanilide and carbamazepine in the presence of H₂¹⁸O₂ resulted in almost complete incorporation of¹⁸O into the corresponding products, thus establishing that these reactions are peroxygenations. The deethylation of phenacetin- d₁ showed an observed intramolecular deuterium isotope effect [( k_H/ k_D)_obs] of 3.1±0.2, which is consistent with the existence of a cytochrome P450-like intermediate in the reaction cycle of APOs. Our results indicate that fungal peroxygenases may be useful biocatalytic tools to prepare pharmacologically relevant drug metabolites.

Keywords: Peroxidase; Peroxygenation; Hydroxylation; O; -Dealkylation; N; -Dealkylation; Cytochrome P450

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Biochemical Pharmacology (v.82, #7)

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Biochemical Pharmacology (v.82, #7)