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Concept: Cytochrome P450


Bright-red colors in vertebrates are commonly involved in sexual, social, and interspecific signaling [1-8] and are largely produced by ketocarotenoid pigments. In land birds, ketocarotenoids such as astaxanthin are usually metabolically derived via ketolation of dietary yellow carotenoids [9, 10]. However, the molecular basis of this gene-environment mechanism has remained obscure. Here we use the yellowbeak mutation in the zebra finch (Taeniopygia guttata) to investigate the genetic basis of red coloration. Wild-type ketocarotenoids were absent in the beak and tarsus of yellowbeak birds. The yellowbeak mutation mapped to chromosome 8, close to a cluster of cytochrome P450 loci (CYP2J2-like) that are candidates for carotenoid ketolases. The wild-type zebra finch genome was found to have three intact genes in this cluster: CYP2J19A, CYP2J19B, and CYP2J40. In yellowbeak, there are multiple mutations: loss of a complete CYP2J19 gene, a modified remaining CYP2J19 gene (CYP2J19(yb)), and a non-synonymous SNP in CYP2J40. In wild-type birds, CYP2J19 loci are expressed in ketocarotenoid-containing tissues: CYP2J19A only in the retina and CYP2J19B in the beak and tarsus and to a variable extent in the retina. In contrast, expression of CYP2J19(yb) is barely detectable in the beak of yellowbeak birds. CYP2J40 has broad tissue expression and shows no differences between wild-type and yellowbeak. Our results indicate that CYP2J19 genes are strong candidates for the carotenoid ketolase and imply that ketolation occurs in the integument in zebra finches. Since cytochrome P450 enzymes include key detoxification enzymes, our results raise the intriguing possibility that red coloration may be an honest signal of detoxification ability.

Concepts: DNA, Gene, Genetics, Gene expression, Evolution, Chromosome, Cytochrome P450, Zebra Finch


Adverse drug reactions and interactions are among the major causes of death in the United States. Antidepressants have been reported as causing suicide and homicide and share the class attribute of frequently producing akathisia, a state of severe restlessness associated with thoughts of death and violence. Medical examiners can now identify some pharmacogenetic interactions that cause drugs, deemed safe for most, to be lethal to others. Such deaths do not yet include medication-induced, akathisia-related suicides and homicides. An extrapyramidal side effect, akathisia is a manifestation of drug toxicity whose causes lie, inter alia, in drugs, doses, and co-prescribed medications that inhibit and compete for metabolizing enzymes, which may themselves be defective. In this paper, we report our investigation into adverse drug reactions/interactions in three persons who committed homicide, two also intending suicide, while on antidepressants prescribed for stressful life events. Their histories of medication use, adverse reactions and reasons for changes in medications are presented. DNA samples were screened for variants in the cytochrome P450 gene family; that produce drug metabolizing enzymes. All three cases exhibit genotype-based diminished metabolic capability that, in combination with their enzyme inhibiting/competing medications, decreased metabolism further and are the likely cause of these catastrophic events.

Concepts: Protein, Pharmacology, Metabolism, Cytochrome P450, Enzyme inhibitor, Adverse drug reaction, Pharmaceutical drug, Suicide


Acetaminophen (paracetamol) is one of the most common medications used for management of pain in the world. There is lack of consensus about the mechanism of action, and concern about the possibility of adverse effects on reproductive health.

Concepts: Health, Influenza, Cytochrome P450, Paracetamol, Adverse drug reaction, World, Adverse effect


Red yeast rice (RYR) is made by fermenting the yeast Monascus purpureus over rice. It is a source of natural red food colorants, a food garnish and a traditional medication. Results of the current study demonstrated that polar fractions of the RYR preparations contained herbal-drug interaction activity, which if left unremoved, enhanced P-glycoprotein activity and inhibited the major drug metabolizing cytochromes P450, i,e, CYP 1A2, 2C9 and 3A4. The data from Caco-2 cell absorption and animal model studies further demonstrated that the pharmacokinetic modulation effect by RYR preparations containing the polar fractions (“untreated” preparation) was greater than that from RYR preparations with the polar fractions removed (“treated” preparation). The data indicates a potential for herb-drug interactions to be present in RYR commonly sold as nutritional supplements when the polar fractions are not removed and this should be taken into consideration when RYR is consumed with medications, including verapamil.

Concepts: Protein, Pharmacology, Metabolism, Nutrition, Model organism, Cytochrome P450, Red yeast rice, Monascus purpureus


Head blight, which is caused by mycotoxin-producing fungi of the genus Fusarium, is an economically important crop disease. We assessed the potential of host-induced gene silencing targeting the fungal cytochrome P450 lanosterol C-14α-demethylase (CYP51) genes, which are essential for ergosterol biosynthesis, to restrict fungal infection. In axenic cultures of Fusarium graminearum, in vitro feeding of CYP3RNA, a 791-nt double-stranded (ds)RNA complementary to CYP51A, CYP51B, and CYP51C, resulted in growth inhibition [half-maximum growth inhibition (IC50) = 1.2 nM] as well as altered fungal morphology, similar to that observed after treatment with the azole fungicide tebuconazole, for which the CYP51 enzyme is a target. Expression of the same dsRNA in Arabidopsis and barley rendered susceptible plants highly resistant to fungal infection. Microscopic analysis revealed that mycelium formation on CYP3RNA-expressing leaves was restricted to the inoculation sites, and that inoculated barley caryopses were virtually free of fungal hyphae. This inhibition of fungal growth correlated with in planta production of siRNAs corresponding to the targeted CYP51 sequences, as well as highly efficient silencing of the fungal CYP51 genes. The high efficiency of fungal inhibition suggests that host-induced gene-silencing targeting of the CYP51 genes is an alternative to chemical treatments for the control of devastating fungal diseases.

Concepts: Bacteria, Biology, RNA, Fungus, Hypha, Fusarium, Cytochrome P450, Ascomycota


Cytochrome P450 oxidoreductase (POR) is known as the sole electron donor in the metabolism of drugs by cytochrome P450 (CYP) enzymes in human. However, little is known about the effect of polymorphic variants of POR on drug metabolic activities of CYP3A4 and CYP2B6. In order to better understand the mechanism of the activity of CYPs affected by polymorphic variants of POR, six full-length mutants of POR (e.g., Y181D, A287P, K49N, A115V, S244C and G413S) were designed and then co-expressed with CYP3A4 and CYP2B6 in the baculovirus-Sf9 insect cells to determine their kinetic parameters. Surprisingly, both mutants, Y181D and A287P in POR completely inhibited the CYP3A4 activity with testosterone, while the catalytic activity of CYP2B6 with bupropion was reduced to approximately ~70% of wild-type activity by Y181D and A287P mutations. In addition, the mutant K49N of POR increased the CLint (Vmax/Km) of CYP3A4 up to more than 31% of wild-type, while it reduced the catalytic efficiency of CYP2B6 to 74% of wild-type. Moreover, CLint values of CYP3A4-POR (A115V, G413S) were increased up to 36% and 65% of wild-type respectively. However, there were no appreciable effects observed by the remaining two mutants of POR (i.e., A115V and G413S) on activities of CYP2B6. In conclusion, the extent to which the catalytic activities of CYP were altered did not only depend on the specific POR mutations but also on the isoforms of different CYP redox partners. Thereby, we proposed that the POR-mutant patients should be carefully monitored for the activity of CYP3A4 and CYP2B6 on the prescribed medication.

Concepts: Metabolism, Enzyme, Electrochemistry, Catalysis, Nitrogen, Cytochrome P450, P450-containing systems, Cytochrome P450 reductase


Carfilzomib, an irreversible proteasome inhibitor, has a favorable safety profile and significant antitumor activity in patients with relapsed and refractory multiple myeloma (MM). Here we summarize the clinical pharmacokinetics (PK), metabolism, and drug-drug interaction (DDI) profile of carfilzomib. The PK of carfilzomib, infused over 2-10 minutes, was evaluated in patients with solid tumors or MM. Metabolites of carfilzomib were characterized in patient plasma and urine samples. In vitro drug metabolism and DDI studies were conducted in human liver microsomes and hepatocytes. A clinical DDI study was conducted in patients with solid tumors to evaluate the effect of carfilzomib on CYP3A activity. Plasma concentrations of carfilzomib declined rapidly and in a biphasic manner after intravenous administration. The systemic half-life was short and the systemic clearance rate was higher than hepatic blood flow. Carfilzomib was cleared largely extrahepatically via peptidase cleavage and epoxide hydrolysis. Cytochrome P450-mediated metabolism played a minor role, suggesting that coadministration of P450 inhibitors or inducers is unlikely to change its PK profile. Carfilzomib showed direct and time-dependent inhibition of CYP3A in human liver microsome preparations and exposure to carfilzomib resulted in reductions in CYP3A and 1A2 gene expression in cultured human hepatocytes. However, administration of carfilzomib did not affect the PK of midazolam in patients with solid tumors, and there were no safety signals indicative of potential drug interactions. We conclude that the rapid systemic clearance and short half-life of carfilzomib limit clinically significant DDI.

Concepts: Pharmacology, Cancer, Liver, Glycogen, Cytochrome P450, Proteasome, Drug metabolism, Hepatocyte


Cytochrome P450 side-chain cleavage enzyme (CYP11A1) catalyses the first and rate-limiting step of steroidogenesis, the conversion of cholesterol to pregnenolone. CYP11A1 deficiency is commonly associated with adrenal insufficiency, and in 46,XY individuals, with variable degrees of disorder of sex development (DSD).

Concepts: Testosterone, Cytochrome P450, Steroid, CYP17A1


Sutherlandia frutescens (ST) is a popular medicinal herb widely consumed in Africa by people living with HIV/AIDS. Concomitant use with antiretroviral drugs has generated concerns of herb-drug interaction. This study investigated the inhibitory effects of the crude extracts of ST on the major cytochrome P450 isozymes employing pooled human liver microsomes. Its effect on the metabolic clearance of midazolam using cryopreserved hepatocytes was also monitored. The potential of ST to inhibit human ATP-binding cassette (ABC) transporters (P-gp and BCRP) and the human organic anion transporting polypeptide (OATP1B1 and OATP1B3) activity was assessed using cell lines overexpressing the transporter proteins. ST showed inhibitory potency for CYP1A2 (IC(50) = 41.0 μg/mL), CYP2A6 (IC(50) = 160 μg/mL), CYP2B6 (IC(50) = 20.0 μg/mL), CYP2C8 (IC(50) = 22.4 μg/mL), CYP2C9 (IC(50) = 23.0 μg/mL), CYP2C19 (IC(50) = 35.9 μg/mL) and CYP3A4/5 (IC(50,) = 17.5 μg/mL [with midazolam1'-hydroxylation]; IC(50) = 28.3 μg/mL [with testosterone 6β-hydroxylation]). Time-dependent (irreversible) inhibition by ST was observed for CYP3A4/5 (KI = 296 μg/mL, kinact = 0.063 min(-1)) under the conditions of this study. ST also delays the production of midazolam metabolites in the hepatocytes, decreasing its clearance by 40%. Further, ST inhibited P-gp (IC(50) = 324.8 μg/mL); OATP1B1 (IC(50) = 10.4 μg/mL, and of OATP1B3 (IC(50) = 6.6 μg/mL). The result indicates the potential for HDI between ST and the substrates of the affected enzymes, if sufficient in vivo concentration of ST is attained.

Concepts: AIDS, Metabolism, Enzyme, Liver, Glycogen, Cytochrome P450, Transport, Sutherlandia frutescens


The disposition of ertugliflozin (PF-04971729), an orally active selective inhibitor of the sodium-dependent glucose cotransporter 2, was studied after a single 25-mg oral dose of [(14)C]-PF-04971729 to healthy human subjects. Mass balance was achieved with approximately 91% of the administered dose recovered in urine and feces. The total administered radioactivity excreted in feces and urine was 40.9% and 50.2%, respectively. The absorption of PF-04971729 in humans was rapid with a T(max) at ~ 1.0 h. Of the total radioactivity excreted in feces and urine, unchanged PF-04971729 collectively accounted for ~ 35.3% of the dose, suggestive of moderate metabolic elimination in humans. The principal biotransformation pathway involved glucuronidation of the glycoside hydroxyl groups to yield three regioisomeric metabolites M4a, M4b and M4c (~39.3% of the dose in urine) of which M4c was the major regioisomer (~31.7% of the dose). The structure of M4a and M4c were confirmed to be PF-04971729-4-O-β- and -3-O-β-glucuronide, respectively, via comparison of the HPLC retention time and mass spectra with authentic standards. A minor metabolic fate involved oxidation by cytochrome P450 to yield monohydroxylated metabolites M1 and M3 and des-ethyl PF-04971729 (M2), which accounted for ~5.2% of the dose in excreta. In plasma, unchanged PF-04971729 and the corresponding 4-O-β- (M4a) and 3-O-β- (M4c) glucuronides were the principal components, which accounted for 49.9, 12.2 and 24.1% of the circulating radioactivity. Overall, these data suggest that PF-04971729 is well absorbed in humans, and eliminated largely via glucuronidation.

Concepts: Alcohol, Metabolism, Nutrition, Cytochrome P450, Steroid, Pharmacokinetics, Carbohydrate, Excretion