ABSTRACT
BACKGROUND: Fluorine plays a significant role in agrochemical science because approximately 25% of herbicides licensed worldwide contain this element. In a pool of previously synthesized benzoxazinones, some compounds contained fluorine and demonstrated inhibitory activities against protoporphyrinogen IX oxidase (PPO). Therefore, three data sets of benzoxazinone derivatives with known inhibitory activity against PPO were employed to build a multivariate image analysis applied to a quantitative structure-activity relationships (MIA-QSAR) model to identify improved analogs with at least one fluorine substituent. RESULTS: The QSAR model was vigorously validated and demonstrated to be highly predictive (r2 = 0.85, q2 = 0.71, and r2 pred = 0.88); thus, the model can provide reliable estimations for the PPO inhibitory activity of unknown derivatives. From these compounds, a couple of N-substituted benzoxazinones that contained the -CH2CHF2 group were found with predicted pKi values larger than 8 (Ki in mol L-1) and higher lipophilicity than the most active data set compounds. In addition, we carried out a systematic investigation of the binding mode of PPO by performing computational docking followed by molecular dynamics simulations. The proposed binding mode was consistent with experimental studies, and several potential key residues were identified. CONCLUSION: Two new proposed benzoxazinones exhibited better performance than compounds of the data set, and fluorine substituents played pivotal roles in describing the biological activities. © 2024 Society of Chemical Industry.
Subject(s)
Benzoxazines , Enzyme Inhibitors , Molecular Docking Simulation , Molecular Dynamics Simulation , Protoporphyrinogen Oxidase , Quantitative Structure-Activity Relationship , Protoporphyrinogen Oxidase/antagonists & inhibitors , Protoporphyrinogen Oxidase/chemistry , Protoporphyrinogen Oxidase/metabolism , Benzoxazines/chemistry , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Herbicides/chemistry , Herbicides/pharmacology , Halogenation , Molecular Structure , Drug DesignABSTRACT
Sumatran fleabane (Conyza sumatrensis [Retz.] E. Walker) can be found in many different agricultural environments and impact different crops, such as soybeans and corn. It is believed that the application of burndown and preemergence herbicides in the off-season are effective in controlling Sumatran fleabane in soybean crops. The objective was to evaluate the effectiveness of burndown and preemergence herbicides in the off-season, with one or two applications, in the control of Sumatran fleabane in soybean cultivation. Five field experiments were conducted in Maripá, state of Paraná (PR), Brazil. The treatments consisted of the application of burndown herbicides in combinations with preemergence ones, with one or two applications. Control of Sumatran fleabane and soybean yield were evaluated. With the set of experiments, it is highlighted that the strategy combining more applications, with different herbicides, burndown and preemergence, is more promising in the control of Sumatran fleabane. When comparing synthetic auxins, dicamba and triclopyr stand out. For sequential application, worse performance was observed for diquat. Combinations between burndown and preemergence herbicides were effective in controlling Sumatran fleabane, for pre sowing application in soybean. With emphasis on managements with sequential applications of saflufenacil with glufosinate or glyphosate. The strategy combining more applications, with different herbicides, burndown and preemergence herbicides, is more promising in the control of Sumatran fleabane.
Subject(s)
Plant Growth Regulators/analysis , Glycine max/growth & development , Conyza/drug effects , Protoporphyrinogen Oxidase/antagonists & inhibitors , Herbicides , Plant WeedsABSTRACT
Weeds can cause significant agricultural yield losses, and the morning-glory species (Ipomoea spp.) has stood out in several crops. To control morning-glories we can use herbicides inhibiting the protoporphyrinogen IX oxidase enzyme in addition to glyphosate, a herbicide that this weed is intolerant to. The objective was to test the efficacy of application of isolates and mixtures of glyphosate (Roundup Original®) with carfentrazone-ethyl (Aurora®) and saflufenacil (Heat®) to control I. hederifolia in two weed growth stages. Treatments consisted of: isolated application of (i) carfentrazone-ethyl (50 and 75 mL l.h. ha-1), (ii) saflufenacil (35 and 50 g l.h. ha-1, and (iii) glyphosate (2 and 4 L l.h. ha-1; and mixtures of (iv) carfentrazone-ethyl+glyphosate and (v) saflufenacil+glyphosate (both in the lowest dose). Applications were performed on plants with 6-8 and 15-20 leaves, maintaining herbicide-free checks for both plant growth stages. Mixture of carfentrazone-ethyl and saflufenacil with glyphosate increases the efficacy of control of I. hederifolia, compared to herbicide isolate applications. Mixture of 2 L ha-1 + 50 mL ha-1 of glyphosate+carfentrazone-ethyl provides more efficient and faster control of I. hederifolia, mainly when the plants have 6-8 leaves.(AU)
As plantas daninhas podem causar perdas significativas de produtividade na agricultura, dentre as quais se destacam as cordas-de-viola (Ipomoea spp.) em diversos cultivos. Para seu controle podem ser utilizados herbicidas inibidores da enzima protoporfirinogênio IX oxidase em complementação ao glyphosate, ao qual essa planta daninha é tolerante. O objetivo foi testar a eficácia de aplicações isoladas e em mistura de glyphosate (Roundup Original®) com carfentrazone-ethyl (Aurora®) e saflufenacil (Heat®) no controle de I. hederifolia em dois estádios de desenvolvimento da planta daninha. Os tratamentos foram: aplicação isolada de (i) carfentrazone-ethyl (50 e 75 mL p.c. ha-1), (ii) saflufenacil (35 e 50 g p.c. ha-1), e (iii) glyphosate (2 e 4 L p.c. ha-1); e em mistura de (iv) carfentrazone-ethyl+glyphosate e (v) saflufenacil+glyphosate (ambos na menor dose). As aplicações ocorreram em plantas de 6-8 folhas e 15-20 folhas, mantendo-se testemunhas sem aplicação para esses dois estádios. A mistura dos herbicidas carfentrazone-ethyl e saflufenacil com glyphosate proporciona aumento na eficácia de controle de I. hederifolia, em relação à aplicação dos herbicidas isolados. A mistura de glyphosate+carfentrazone-ethyl na dose de 2 L ha-1 + 50 mL ha-1 proporciona controle mais eficaz e mais rápido de I. hederifolia, principalmente quando as plantas estão no estádio de 6-8 folhas.(AU)
Subject(s)
Ipomoea , Herbicides/administration & dosage , Protoporphyrinogen Oxidase/analysis , Plant WeedsABSTRACT
Weeds can cause significant agricultural yield losses, and the morning-glory species (Ipomoea spp.) has stood out in several crops. To control morning-glories we can use herbicides inhibiting the protoporphyrinogen IX oxidase enzyme in addition to glyphosate, a herbicide that this weed is intolerant to. The objective was to test the efficacy of application of isolates and mixtures of glyphosate (Roundup Original®) with carfentrazone-ethyl (Aurora®) and saflufenacil (Heat®) to control I. hederifolia in two weed growth stages. Treatments consisted of: isolated application of (i) carfentrazone-ethyl (50 and 75 mL l.h. ha-1), (ii) saflufenacil (35 and 50 g l.h. ha-1, and (iii) glyphosate (2 and 4 L l.h. ha-1; and mixtures of (iv) carfentrazone-ethyl+glyphosate and (v) saflufenacil+glyphosate (both in the lowest dose). Applications were performed on plants with 6-8 and 15-20 leaves, maintaining herbicide-free checks for both plant growth stages. Mixture of carfentrazone-ethyl and saflufenacil with glyphosate increases the efficacy of control of I. hederifolia, compared to herbicide isolate applications. Mixture of 2 L ha-1 + 50 mL ha-1 of glyphosate+carfentrazone-ethyl provides more efficient and faster control of I. hederifolia, mainly when the plants have 6-8 leaves.
As plantas daninhas podem causar perdas significativas de produtividade na agricultura, dentre as quais se destacam as cordas-de-viola (Ipomoea spp.) em diversos cultivos. Para seu controle podem ser utilizados herbicidas inibidores da enzima protoporfirinogênio IX oxidase em complementação ao glyphosate, ao qual essa planta daninha é tolerante. O objetivo foi testar a eficácia de aplicações isoladas e em mistura de glyphosate (Roundup Original®) com carfentrazone-ethyl (Aurora®) e saflufenacil (Heat®) no controle de I. hederifolia em dois estádios de desenvolvimento da planta daninha. Os tratamentos foram: aplicação isolada de (i) carfentrazone-ethyl (50 e 75 mL p.c. ha-1), (ii) saflufenacil (35 e 50 g p.c. ha-1), e (iii) glyphosate (2 e 4 L p.c. ha-1); e em mistura de (iv) carfentrazone-ethyl+glyphosate e (v) saflufenacil+glyphosate (ambos na menor dose). As aplicações ocorreram em plantas de 6-8 folhas e 15-20 folhas, mantendo-se testemunhas sem aplicação para esses dois estádios. A mistura dos herbicidas carfentrazone-ethyl e saflufenacil com glyphosate proporciona aumento na eficácia de controle de I. hederifolia, em relação à aplicação dos herbicidas isolados. A mistura de glyphosate+carfentrazone-ethyl na dose de 2 L ha-1 + 50 mL ha-1 proporciona controle mais eficaz e mais rápido de I. hederifolia, principalmente quando as plantas estão no estádio de 6-8 folhas.
Subject(s)
Herbicides/administration & dosage , Ipomoea , Protoporphyrinogen Oxidase/analysis , Plant WeedsABSTRACT
Este estudo teve como objetivo avaliar a eficiência de herbicidas inibidores da acetolactato sintase (ALS) e protoporfirinogênio oxidase (PROTOX) no controle de Bidens pilosa sob duas condições hídricas, bem como determinar a influência deste déficit hídrico sob o conteúdo de carboidratos e proteínas solúveis da planta daninha. O delineamento experimental utilizado foi inteiramente casualizado com os tratamentos, com quatro repetições, dispostos em um esquema fatorial 4x2, sendo quatro herbicidas (fomesafen, lactofen, chlorimuron-ethyl e imazethapyr, na dose recomendada pelo fabricante) e duas condições hídricas (-0,5 MPa e -0,01 MPa). Aos 7, 14, 21 e 28 dias após a aplicação (DAA) dos tratamentos foi avaliada de forma visual a eficiência de controle dos herbicidas. Para a determinação dos solutos orgânicos foram coletadas plantas às 24, 48, 72 e 96 horas após a aplicação (HAA). Os herbicidas controlaram de forma eficiente as plantas de B. pilosa, com exceção do lactofen, enquanto que o déficit hídrico afetou a eficiência de controle de todos os herbicidas testados. O conteúdo de carboidratos solúveis aumentou com a imposição do déficit hídrico, contudo, os herbicidas e o déficit hídrico proporcionaram redução de proteínas solúveis nas plantas de B. pilosa.
The objective of this work was to evaluate conditions the effectiveness of acetolactate synthase (ALS) and protoporphyrinogen oxidase (PROTOX) inhibitors in the Bidens pilosa control under two water deficit conditions, as well as to determine the influence of water deficit under the contents of soluble carbohydrates and protein of weed. The experimental design was randomized completely design with the treatments, with four replications, setup in a factorial scheme 4x2, with four herbicides (fomesafen lactofen, chlorimuron-ethyl and imazethapyr), and two water conditions (-0.5 MPa and -0.01MPa). At 7, 14, 21 and 28 days after application (DAA), was assessed visually control efficiency of herbicides. For the determination of organic solutes plants were collected at 24, 48, 72 and 96 hours after application (HAA). Herbicides controlled efficiently plants of B. pilosa, except lactofen, whereas the water deficit affected the efficiency of control of all the herbicides. The soluble carbohydrate content increased with the imposition of water deficit, however, herbicides and water deficit further reduction of soluble proteins in plants of B. pilosa.
Subject(s)
Acetolactate Synthase , Bidens , Efficiency , Protoporphyrinogen Oxidase , Plant Weeds , HerbicidesABSTRACT
BACKGROUND: A partial deficiency in Protoporphyrinogen oxidase (PPOX) produces the mixed disorder Variegate Porphyria (VP), the second acute porphyria more frequent in Argentina. Identification of patients with an overt VP is absolutely important because treatment depends on an accurate diagnosis but more critical is the identification of asymptomatic relatives to avoid acute attacks which may progress to death. METHODS: We have studied at molecular level 18 new Argentinean patients biochemically diagnosed as VP. PPOX gene was amplified in one or in twelve PCR reactions. All coding exons, flanking intronic and promoter regions were manual or automatically sequenced. For RT-PCR studies RNA was retrotranscripted, amplified and sequenced. PPOX activity in those families carrying a new and uncharacterized mutation was performed. RESULTS: All affected individuals harboured mutations in heterozygous state. Nine novel mutations and 3 already reported mutations were identified. Six of the novel mutations were single nucleotide substitutions, 2 were small deletions and one a small insertion. Three single nucleotide substitutions and the insertion were at exon-intron boundaries. Two of the single nucleotide substitutions, c.471G>A and c.807G>A and the insertion (c.388+3insT) were close to the splice donor sites in exons 5, 7 and intron 4 respectively. The other single nucleotide substitution was a transversion in the last base of intron 7, g.3912G>C (c.808-1G>C) so altering the consensus acceptor splice site. However, only in the first case the abnormal band showing the skipping of exon 5 was detected. The other single nucleotide substitutions were transversions: c.101A>T, c.995G>C and c.670 T>G that result in p.E34V, p.G332A and W224G aminoacid substitutions in exons 3, 10 and 7 respectively. Activity measurements indicate that these mutations reduced about 50% PPOX activity and also that they co-segregate with this reduced activity value. Two frameshift mutations, c.133delT and c.925delA, were detected in exons 3 and 9 respectively. The first leads to an early termination signal 22 codons downstream (p.S45fsX67) and the second leads to a stop codon 5 codons downstream (p.I309fsX314). One reported mutation was a missense mutation (p.G232R) and 2 were frameshift mutations: c.1082insC and 1043insT. The last mutation was detected in six new apparently unrelated Argentinean families. CONCLUSION: Molecular analysis in available family members revealed 14 individuals who were silent carriers of VP. Molecular techniques represent the most accurate approach to identify unaffected carriers and to provide accurate genetic counselling for asymptomatic individuals. The initial screening includes the insertion search.
Subject(s)
Flavoproteins/genetics , Mitochondrial Proteins/genetics , Porphyria, Variegate/genetics , Protoporphyrinogen Oxidase/genetics , Adolescent , Adult , Exons , Female , Frameshift Mutation , Genetic Carrier Screening , Heme/biosynthesis , Humans , Male , Middle Aged , Mutation, Missense , Polymerase Chain Reaction , Porphyria, Variegate/metabolism , Sequence Analysis, DNAABSTRACT
Variegate porphyria (VP) results from a hereditary deficiency of protoporphyrinogen oxidase (PPOX) that is transmitted in an autosomal dominan fashion. The diagnosis is based on the clinical symptoms and is confirmed biochemically. Sometimes, however, these diagnostic tools reveal limitations in establishing the definitive diagnosis of the prevailing type of acute porphyria. In these patients, molecular genetic analyses can be useful. We performed molecular genetic studies in 13 Chilean families by PCR amplification of the PPOX gene, conformation sensitive gel electrophoresis, and automated DNA sequencing. In five symptomatic patients from different families, respectively, the biochemical data confirmed the diagnosis of VP. In seven other families, however, the biochemical studies were not conclusive. Furthermore, the original biochemical analysis in one clinically severely affected patient from a further family even suggested the diagnosis of erythropoietic protoporphyria (EPP). Beside the respective index patients, we studied 78 asymptomatic family members and 50 healthy, unrelated individuals for control purposes. In five families, the previous diagnosis of VP could be confirmed genetically. Further, half of the asymptomatic relatives revealed a mutation in the PPOX gene, consisting of three missense mutations and two deletion mutations. Mutation R168H that had been already described previously in German VP families was found in a Chilean family of German origin. Further, two novel missense mutations, designated L74P and G232S, could be detected. In four Chilean families, we found the deletion 1330deICT that had also been previously described in three Swedish VP families. The second deletion, 1239delTACAC, has not been described anywhere else but Chile and could be identified in seven families. One patient who was initially diagnosed with EPP turned out to be a compound heterozygote for mutations on both alleles of the PPOX gene. In conclusion, our molecular genetic analyses unequivocally confirmed the diagnosis of VP in seven families who originally had revealed inconclusive biochemical data. Further, early genetic analysis allows for the identification of asymptomatic mutation carriers, thereby offering the possibility of adequate counselling and the prevention of potentially life-threatening acute porphyric attacks.
Subject(s)
Porphyria, Variegate/genetics , Protoporphyrinogen Oxidase/genetics , Chile , Flavoproteins/genetics , Genetic Predisposition to Disease , Humans , Mitochondrial Proteins/genetics , Mutation , Porphyria, Variegate/diagnosis , Porphyria, Variegate/enzymologyABSTRACT
Variegate porphyria (VP) results from a hereditary deficiency of protoporphyrinogen oxidase (PPOX) that is transmitted in an autosomal dominan fashion. The diagnosis is based on the clinical symptoms and is confirmed biochemically. Sometimes, however, these diagnostic tools reveal limitations in establishing the definitive diagnosis of the prevailing type of acute porphyria. In these patients, molecular genetic analyses can be useful. We performed molecular genetic studies in 13 Chilean families by PCR amplification of the PPOX gene, conformation sensitive gel electrophoresis, and automated DNA sequencing. In five symptomatic patients from different families, respectively, the biochemical data confirmed the diagnosis of VP. In seven other families, however, the biochemical studies were not conclusive. Furthermore, the original biochemical analysis in one clinically severely affected patient from a further family even suggested the diagnosis of erythropoietic protoporphyria (EPP). Beside the respective index patients, we studied 78 asymptomatic family members and 50 healthy, unrelated individuals for control purposes. In five families, the previous diagnosis of VP could be confirmed genetically. Further, half of the asymptomatic relatives revealed a mutation in the PPOX gene, consisting of three missense mutations and two deletion mutations. Mutation R168H that had been already described previously in German VP families was found in a Chilean family of German origin. Further, two novel missense mutations, designated L74P and G232S, could be detected. In four Chilean families, we found the deletion 1330deICT that had also been previously described in three Swedish VP families. The second deletion, 1239delTACAC, has not been described anywhere else but Chile and could be identified in seven families. One patient who was initially diagnosed with EPP turned out to be a compound heterozygote for mutations on both alíeles of the PPOX gene. In conclusion, our molecular genetic analyses unequivocally confirmed the diagnosis of VP in seven families who originally had revealed inconclusive biochemical data. Further, early genetic analysis allows for the identification of asymptomatic mutation carriers, thereby offering the possibility of adequate counselling and the prevention of potentially life-threatening acute porphyric attacks.
La porfiria variegata (PV), enfermedad de origen genético con forma de herencia autosómica dominante, se debe a deficiencia en la actividad protoporfirinógeno oxidasa (PPOX). Su diagnóstico se basa en antecedentes clínicos y se confirma con análisis bioquímicos. Éstos, en algunos casos, pueden presentar limitaciones para establecer el diagnóstico definitivo de la variedad de porfiria aguda, situación en que el estudio genético molecular puede resultar útil. Se efectuó estudio genético en trece familias chilenas usando amplificación del gen PPOX por PCR, electroforesis conformacional y secuenciación automática de DNA. Cinco de estas familias incluían pacientes índices sintomáticos con diagnóstico bioquímico establecido de PV; otras siete familias incluían pacientes índices con estudio bioquímico no concluyente de la variedad de porfiria aguda y, finalmente, una familia con diagnóstico previo de protoporfiria eritropoyética (PPE). Además, se estudiaron 78 familiares asintomáticos y 50 personas sanas, no relacionadas, como controles. En cinco familias el estudio genético confirmó el diagnóstico bioquímico previo de PV. El 50% de los familiares asintomáticos resultaron ser portadores de una mutación en el gen PPOX. Se identificaron tres mutaciones por sustitución de bases: la R168H, descrita en familias de origen alemán y dos nuevas mutaciones, designadas L74P y G232S. También se identificaron dos mutaciones por deleción de bases designadas 1330delCT y la 1239delTACAC. La primera, que había sido descrita previamente en tres familias suecas, se encontró en cuatro familias chilenas. La segunda se encontró en siete familias y no ha sido descrita previamente. El estudio genético permitió mostrar que un paciente que originalmente fue diagnosticado con PPE correspondía a un heterocigoto compuesto para dos mutaciones en el gen PPOX. En conclusión, los estudios moleculares permitieron confirmar el diagnóstico de PV en cinco familias, efectuar diagnóstico de PV en familias en las cuales los datos bioquímicos no eran concluyentes, corregir el diagnóstico original en una familia e identificar portadores asintomáticos entre los familiares de los pacientes índices. Los estudios genéticos moleculares ayudan a realizar un adecuado consejo genético a pacientes y familiares y hace posible practicar prevención de las crisis agudas de porfiria, las que son potencialmente mortales.
Subject(s)
Humans , Porphyria, Variegate/genetics , Protoporphyrinogen Oxidase/genetics , Chile , Flavoproteins/genetics , Genetic Predisposition to Disease , Mutation , Mitochondrial Proteins/genetics , Porphyria, Variegate/diagnosis , Porphyria, Variegate/enzymologyABSTRACT
A 7-year-old Chilean boy presented with severe photosensitivity, blistering, erosions and scarring on sun-exposed areas of the body since the age of 6 months. Additionally, he showed a short stature and shortening of the fingers. Laboratory examination revealed greatly elevated protoporphyrin levels in the blood. Such biochemical findings can be observed in homozygous variants of usually autosomal dominantly inherited acute porphyrias such as variegate porphyria (VP) and hereditary coproporphyria, which usually do not become manifest before the second or third decade of life in heterozygotes. Using polymerase chain reaction-based techniques we identified a missense mutation in exon 7 on the paternal allele and a frameshift mutation in exon 13 on the maternal allele of the protoporphyrinogen oxidase gene that harbours the mutations underlying VP. This is the first homozygous case of VP in South America. As VP represents the most frequent type of acute porphyria not only in Chile but also in South Africa, more such cases could be expected in the future, particularly because a founder mutation for this disease has already been described in the Chilean and South African population.
Subject(s)
Fingers/abnormalities , Porphyria, Variegate/genetics , Protoporphyrinogen Oxidase/genetics , Child , Chile/epidemiology , DNA Mutational Analysis , Frameshift Mutation/genetics , Homozygote , Humans , Male , Mutation, Missense/genetics , Photosensitivity Disorders/genetics , Pigmentation Disorders/genetics , Pigmentation Disorders/pathology , Porphyria, Variegate/epidemiology , Porphyria, Variegate/pathology , Protoporphyrins/analysisABSTRACT
This work was aimed at locating Eucalyptus ESTs corresponding to the PROTOX or PPO enzyme (Protoporphyrinogen IX oxidase, E.C. 1.3.3.4) directly related to resistance to herbicides that promote oxidative stress, changing the functionality of this enzyme. PROTOX, which is the site of action of diphenyl-ether (oxyfluorfen, lactofen, fomesafen), oxadiazole (oxadiazon and oxadiargyl), and aryl triazolinone (sulfentrazone and carfentrazone) herbicides, acts on the synthesis route of porphyrins which is associated with the production of chlorophyll a, catalases, and peroxidases. One cluster and one single read were located, with e-values better than e-70, associated to PROTOX. The alignment results between amino acid sequences indicated that this enzyme is adequately represented in the ESTs database of the FORESTs project
Subject(s)
Catalase/genetics , Eucalyptus/genetics , Herbicides , Protoporphyrinogen Oxidase , Chlorophyll , Databases, Genetic , Expressed Sequence Tags , Heme , Oxidative Stress , PeroxidaseABSTRACT
Resistance to acetolactate synthase (ALS)-inhibiting herbicides in Brazil has been documented for six species. The probability to select biotypes of Euphorbia heterophylla (EPPHL) with multiple resistance increases in the same order of magnitude as the use of other herbicides belonging to only one mechanism of action. The objectives of this work were to evaluate the distribution of resistant populations (R) in the states of the Parana and Santa Catarina; to determine the existence of populations of EPHHL with multiple resistance to ALS and PROTOX inhibitors, and to confirm the occurrence of cross resistance to compounds of these mechanisms of action. Seeds of EPHHL of areas with suspected resistance had been sampled in 97 places during 2003. In the greenhouse experiment samples of each population were sprayed with imazethapyr or fomesafen, at only one rate. To identify the resistant ones they were sprayed with different levels of the herbicides imazethapyr and fomesafen. Later they were sprayed with diverse herbicides of the same mechanisms of action to confirm the multiple/cross resistance. There is widespread distribution in the region of populations with resistance to ALS inhibitors. Some biotypes demonstrated resistance to herbicides from the two mechanisms of action. The resistance factor (FR), or the relation of resistance between R and susceptible biotypes, confirms the existence of two biotypes of EPHHL with cross resistance to several herbicides inhibitors of ALS and PROTOX.
Subject(s)
Acetolactate Synthase/antagonists & inhibitors , Acetolactate Synthase/pharmacology , Drug Resistance, Multiple , Euphorbia/enzymology , Euphorbia/growth & development , Herbicides/pharmacology , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Oxidoreductases Acting on CH-CH Group Donors/pharmacology , Acetolactate Synthase/drug effects , Adaptation, Physiological , Brazil , Environmental Monitoring , Enzyme Inhibitors/pharmacology , Oxidoreductases Acting on CH-CH Group Donors/drug effects , Pest Control , Population Dynamics , Protoporphyrinogen OxidaseABSTRACT
Variegate porphyria (VP; OMIM 176200) is characterized by a partial defect in the activity of protoporphyrinogen oxidase (PPO), the seventh enzyme of the porphyrin-heme biosynthetic pathway. The disease is usually inherited as an autosomal dominant trait displaying incomplete penetrance. In an effort to characterize the spectrum of molecular defects in VP, we identified 3 distinct mutations in 6 VP families from Chile by PCR, heteroduplex analysis, automated sequencing, restriction enzyme digestion and haplotyping analysis. The mutations consisted of 2 deletions and 1 missense mutation, designated 1239delTACAC, 1330delT and R168H. The occurrence of the missense mutation R168H had been reported previously in American, German and Dutch VP families, suggesting that this may represent a frequent recurrent mutation. Interestingly, the mutation 1239delTACAC was found in patients from 4 unrelated families living in different parts of Chile, suggesting that it might represent a common mutation in Chile. Haplotype analysis using 15 microsatellite markers which closely flank the PPO gene on chromosome 1q22, spanning approximately 21 cM, revealed the presence of R168H on different haplotypes in 6 VP patients from 3 unrelated families. In contrast, we found the occurrence of 1239delTACAC on the same chromosome 1 haplotype in 11 mutation carriers from 4 unrelated families with VP. These findings are consistent with R168H representing a hotspot mutation and 1239delTACAC existing as a founder mutation in the PPO gene. Our data comprise the first genetic studies of the porphyrias in South America and will streamline the elucidation of the genetic defects in VP patients from Chile by allowing an initial screening for the founder mutation 1239delTACAC.
Subject(s)
Founder Effect , Mutation , Oxidoreductases Acting on CH-CH Group Donors , Oxidoreductases/genetics , Porphyrias, Hepatic/genetics , Chile , Female , Flavoproteins , Humans , Male , Mitochondrial Proteins , Mutation, Missense , Porphyrias, Hepatic/enzymology , Protoporphyrinogen Oxidase , Sequence DeletionSubject(s)
Mutation/genetics , Oxidoreductases Acting on CH-CH Group Donors , Oxidoreductases/genetics , Porphyrias, Hepatic/enzymology , Porphyrias, Hepatic/genetics , Porphyrins/metabolism , Argentina/epidemiology , Flavoproteins , Genes, Dominant/genetics , Humans , Mitochondrial Proteins , Mutagenesis, Insertional/genetics , Protoporphyrinogen OxidaseSubject(s)
Amino Acid Substitution/genetics , Mutation, Missense/genetics , Oxidoreductases Acting on CH-CH Group Donors , Oxidoreductases/genetics , Porphyrias, Hepatic/enzymology , Porphyrias, Hepatic/genetics , Flavoproteins , Histidine/genetics , Humans , Leucine/genetics , Mitochondrial Proteins , Porphyrias, Hepatic/diagnosis , Proline/genetics , Protoporphyrinogen Oxidase , Valine/geneticsABSTRACT
The use of antineoplastics is common in cancer therapy, and some of them have been associated with the development of porphyria in patients with cancer. However, knowledge of their effects on the haeme metabolic pathway is at present scarce and unclear. So, the present study evaluates the porphyrinogenic ability of nine antineoplastics (both alkylating and non-alkylating). These were tested either alone or in conjunction with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (latent porphyria model) in chick embryos and in mice. The results obtained suggest that the use of cyclophosphamide, azathioprine, 5-fluorouracil, busulphan, procarbazine and hexamethylmelamine be avoided in the treatment of porphyric patients. On the other hand, dacarbazine, chlorambucil and melphalan are non-porphyrinogenic. We also provide evidence showing that neither the presence of the mustard group in the structure of the antineoplastic nor alterations in ferrochelatase or protoporphyrinogen oxidase activities are responsible for the porphyrinogenic ability of cyclophosphamide.