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Recent investigations revealed that the "brittle bone" phenotype in osteogenesis imperfecta (OI) is caused not only by dominant mutations in collagen type I genes, but also by recessively inherited mutations in genes responsible for the post-translational processing of type I procollagen as well as for bone formation. The phenotype of patients with mutations in noncollagen genes overlaps with very severe type III and lethal type II OI caused by mutations in collagen genes. Mutations in genes that encode proteins involved in collagen prolyl 3-hydroxylation (P3H1/CRTAP/CyPB) eliminated Pro986 hydroxylation and caused an increase in modification of collagen helix by prolyl 4-hydroxylase and lysyl hydroxylase. However, the importance of these disturbances in the disease pathomechanism is not known. Loss of complex proteins' function as collagen chaperones may dominate the disease mechanism. The latest findings added to the spectrum of OI-causing and collagen-influencing factors other chaperones (HSP47 and FKBP65) and protein BMP-1, which emphasizes the complexity of collagen folding and secretion as well as their importance in bone formation. Furthermore, mutations in genes encoding transcription factor SP7/Osterix and pigment epithelium-derived factor (PEDF) constitute a novel mechanism for OI, which is independent of changes in biosynthesis and processing of collagen. [ABSTRACT FROM AUTHOR]

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The strain of Absidia coerulea 93 was used to investigate the transformations of C18 steroids: 19-nortestosterone and its 17α-alkyl and ethynyl derivatives. 19--nortestosterone and its 17α-alkyl derivatives were transformed, forming hydroxylated products. It was found that the position of the introduced hydroxyl group depended on the structure of the substrate: 19-nortestosterone underwent hydroxylation at C15, whereas 19-nortestosterone 17α-alkyl derivatives were predominantly hydroxylated at 7α--position. Besides hydroxylation introduction of double bond C6-C7 was observed. It was noticed that 19-nortestosterone 17α-ethynyl derivatives were not transformed in Absidia coerulea culture. [ABSTRACT FROM AUTHOR]

Recent genetic, bioinformatic and biochemical analyses have revealed that many secretory peptides are important components in intercellular signaling that coordinate and specify cellular functions in plants. The signaling peptides discovered in plants thus far can be considered to fall into two broad groups. Peptides from the first group are undergo post-translational modification, such as proline hydroxylation, hydroxyproline arabinosylation or tyrosine sulfation. Peptides from the second group are defined as cysteine-rich peptides (CRPs). The Cys-rich peptides are larger and they contain 4 to 16 cysteine residues. In parallel with the discovery of plant signal peptides, specific receptors for such peptide signals are identified. So far, the receptors for plant peptides that have been identified are members of the receptor-like kinases (RLKs) and the receptor-like proteins (RLPs) families, and most of them contain leucine-rich repeat (LRR) extracellular domain. The present review presents the recent progress in research on small post-translationally modified signal peptides. Recent findings indicate that these peptides are involved in various aspects of plant growth regulation including meristem organization, primary root development, lateral root initiation, vasculature development, organ abscission, and root nodulation.

Cyclophosphamide (CPA) and ifosfamide (IFO) belong to oxazaphosphorine drugs and for a few decades have been widely used for treatment of solid tumours and haematological malignancies. Both drugs are administered in pharmacologically inactive form and require metabolic activation by cytochrome P-450 (CYP). Metabolic transformations taking place under the action of specific CYP isoenzymes lead to the formation of therapeutically essential metabolites and some toxic compounds affecting quality of therapy. The first stage of these conversions is connected with hydroxylation reactions occurring on the C-4 carbon atom within a ring and C-1 atoms of 2-chloroethyl chains. As a result of C-4 hydroxylation 4-hydroxy derivatives (4-OH-CPA and 4-OH-IFO) are formed and remain in tautomeric equilibrium with aldo compounds which in cancer cells spontaneously release cytotoxic phosphoramide mustards and urotoxic acrolein. At the same time hydroxychloroethyl compounds formed during hydroxylation of side-chains are unstable and collapse with the release of inter alia nephro- and neurotoxic chloroacetaldehyde (CAA). Due to formation of toxic metabolites it is essential to use some preventive agents such as mesna and recently examined agmatine. Since CPA and IFO are widely used anticancer drugs, their efficacy is limited not only by their toxicity but also due to occurring resistance. This resistance seems to be a result of changes of expression and activity of enzymes such as CYP and aldehyde dehydrogenase (ALDH) and increase of intracellular levels of glutathione (GSH) and glutathione S-transferase (GST). At present a few methods of overcoming this resistance are being examined including the use of metabolism modulators, antisense oligonucleotides selectively inhibiting gene expression, and introducing genes of some CYP isoenzymes to a cancer tissue.

Transporters of sinusoidal and lateral membranes mediate uptake of inorganic and organic substances to hepatocyte. In hepatocyte lipophilic compounds are biotransformed (hydroxylated and conjugated) and excreted into bile and urine. Vectorial movement of solutes and water from blood to bile is maintained by pumps of ABC superfamily secreting bile salts (bile acid dependent flow) and other solutes: bilirubin, phospholipids, glutathione and inorganic salts (bile acid independent flow).

An influence of hydroxylation phenotype on the concentration of propranolol [corrected] was examined in 52 subjects with hyperlipidemia divided into 4 groups: 1--control, normolipemic, 2--hypercholesterolemic, 3--hypertriglyceridemic, and 4--mixed-form hyperlipidemic. Each study group included extensive metabolizers and one subject characterized by a poor hydroxylation phenotype. Propranolol was given intragastrically at a single dose of 80 mg [corrected]. Blood was sampled within 24 hours following the drug administration. HPLC method was used for determining blood serum concentrations of propranolol. In each study group mean blood serum concentrations of propranolol in poor metabolizers were at maximum in subject with hypertriglyceridemia, at minimum in the normolipemic one, and intermediate in hypercholesterolemic (upper) and mixed-form hyperlipidemic ones. Lipid metabolic disturbances also affected blood serum concentrations. They were the highest in hypertriglyceridemic patients, whereas in hypercholesterolemic were, in early stage of observation, even lower then in normolipemic subjects. Blood serum concentrations of propranolol [corrected] attained minimal values in patients with mixed form of hyperlipidemia. In the light of the present study we can state that hyperlipidemia modifies the blood serum concentrations of propranolol [corrected]. Although, the type of hyperlipidemia and lipophilic propranolol are not the only determinants affecting blood serum concentrations of propranolol, but also a genetic factor, i.e. hydroxylation phenotype may play an important role.

The influence of elevated concentration of lipids in blood on the concentration of drugs in organism was observed in 1976. The following experiments have revealed that pharmacokinetics of lipophilic drugs in hyperlipidemia is altered. The purpose of this paper was to evaluate the effect of hypolipemic treatment on the propranolol pharmacokinetics, to take into account phenotype of hydroxylation and type of primary hyperlipidemia. The study was carried out on 37 patients (34 patients EM and 3 patients PM) with hypercholesterolemia, hypertriglyceridemia and mixed form of hyperlipidemia. Duration of hypolipemic therapy was 30 days. Pharmacokinetic studies were carried out twice i.e. at the onset of the study and following a 30-day period of hypolipemic treatment. Propranolol was given orally as a single dose 80 mg. Blood serum was sampled during administration. HPLC method was used to determine blood serum concentration of propranolol. The one-compartment model was applied for calculation of pharmacokinetic parameters. The obtained results have disclosed that hypolipemic therapy altered pharmacokinetic parameters of propranolol. Intensity and course of these changes depend on the type of hyperlipidemia. The most pronounced changes were observed in patients EM with hypertriglyceridemia. Lowering of propranolol concentration in blood, elevated penetration into tissues and accelerated elimination were revealed (Fig. 3, 4). Similar changes, but lesser intensity were observed in patients with mixed form of hyperlipidemia (Fig 5, 6). Alteration of pharmacokinetic parameters of propranolol in hypercholesterolemic patients were slight and contrasting the patients with hypertriglyceridemia and mixed form of hyperlipidemia. The lowering of cholesterol concentration in blood has slight influence on normalization of propranolol kinetics (Fig 1, 2). In patients with phenotype PM pharmacokinetic parameters of propranolol were changed, under used treatment too. Due to the limited number of patients, conclusions should be carefully drawn. The actual results have disclosed a decrease in lipids concentration, mainly triglycerides, which causes changes in pharmacokinetics of propranolol in patients with phenotype PM as well.

About 5-10% of European white population has a genetically determinant defect of the CYP2D6, one of the enzymes of cytochrome P-450. This defect leads to the impaired metabolism of many drugs including various psychopharmacological agents. The measurement of the hydroxylation of debrisoquine is a laboratory test which allows to identify such an individual. Patients who show an impaired hydroxylation of debrisoquine usually demonstrate severe side effects and poor outcome of psychopharmacotherapy. This depends on whether the administered drug is metabolized the same way as debrisoquine, i.e. in the presence of CYP2D6. The diagnosis of the phenotype of debrisoquine hydroxylation before treatment may allow to select the group of poor metabolizers. This diagnosis can help to identify the appropriate treatment for those patients, i.e. the selection of either a drug which is not metabolized in the presence of CYP2D6 or an alternative form of therapy.

Aromatic hydrocarbons hydroxylase (AHH)--an enzyme of monooxydases group--catalyzes hydroxylation of polycyclic aromatic hydrocarbons yielding compounds of the direct cancerogenic properties. Inducibility determined genetically is a characteristic feature of AHH. Inducibility of AHH in patients with cancer of the lungs is higher than that in healthy population. According to some authors general population may be classified into three groups of : high, moderate, and low degree of AHH inducibility. A significant increase in the incidence of neoplasms related to an exposition to PAH was noted in patients with increased AHH inducibility. These neoplasms include: carcinoma of the lungs, mouth and larynx, cancer of the pharynx and leukoplakia. Moreover, the onset of these neoplasms is earlier than in subjects with moderate and low inducibility of AHH.

The paper presents the general data concerning cytochrome P-448, as well as its participation in the formation of oxygen radicals and active metabolic intermediates, originated during xenobiotics' oxidation. Also, induction of synthesis of cytochrome P-448 (aromatic hydrocarbons hydroxylase), along with the role this phenomenon plays in the initiation of neoplastic process, are discussed.