Mitochondrial Biotransformation of Drugs and Other Xenobiotics

: In vivo biotransformation of exposed chemicals is one of the major factors that determine the concentration and the duration of a substance at the systemic site of effect. Given that toxicity is expressed as a function of two factors, namely dose and time, the type and intensity of the toxicity are directly dependent on the chemical transformation of the exposed parent substance. This dependency involves two different situations. The amount of the chemical reaching the target will be decreased with the extent of metabolism if the parent chemical is toxic. The opposite is true if the metabolite(s) is toxic instead. To date, the liver microsomal fraction in mammals has been justifiably considered the centre of biotransformation reactions as the liver and microsomes (i.e., endoplasmic reticulum component of the cell) possess the most abundant types and quantities of xenobiotic-metabolizing enzymes, especially the cytochrome P450 supergene enzyme family. These enzymes are common in all kingdoms of life, which strongly suggests that the origin of life is common. It is already known that various drugs enter mitochondria by different mechanisms, and this translocation is believed to be responsible for mitochondrial effects that are part of the therapeutic actions of various drugs such as lipid-lowering statins or antidiabetogenic thiazolidindiones. However, the discovery of mitochondrial forms of the xenobiotic-metabolizing enzymes provoked discussions about whether mitochondria metabolize drugs and other chemicals to some extent. This possibility may particularly be important as mitochondria have various critical cellular structures and functions. In the case of in situ generated metabolite(s), when there are adverse interactions with either these structures or functions, various toxic outcomes may appear. In this review, we compiled studies in the literature regarding biotransformation of drugs and other chemicals catalysed by mitochondria, where it is both an initiator and target of toxicity.

Homeostasis of the ER redox state subsequent to proteasome inhibition

Endoplasmic reticulum (ER) maintains within, an oxidative redox state suitable for disulfide bond formation. We monitored the ER redox dynamics subsequent to proteasome inhibition using an ER redox probe ERroGFP S4. Proteasomal inhibition initially led to oxidation of the ER, but gradually the normal redox state was recovered that further led to a reductive state. These events were found to be concomitant with the increase in the both oxidized and reduced glutathione in the microsomal fraction, with a decrease of total intracellular glutathione. The ER reduction was suppressed by pretreatment of a glutathione synthesis inhibitor or by knockdown of ATF4, which induces glutathione-related genes. These results suggested cellular adaptation of ER redox homeostasis: (1) inhibition of proteasome led to accumulation of misfolded proteins and oxidative state in the ER, and (2) the oxidative ER was then reduced by ATF4 activation, followed by influx of glutathione into the ER.

THE EFFECT OF VITAMIN E ON THE BIOCHEMICAL PARAMETERS IN THE EXPERIMENT

The effect of vitamin E on rat liver cytochrome P-450 in experimental acute pancreatitis (AP) was studied. The animals were divided into 4 groups. The obtained data were compared with the indicators of the 1–st group (intact). During the experiment, the development of AP showed a decrease in the content of cytochrome P450 in the microsomal fraction. The administration of vitamin E to animals of the 4th group led to an increase in the content of cytochrome P-450, strengthening the protection of the liver, the abolition of inhibition of the monooxygenase system of the liver.

Decreased ADAM17 expression in the lungs of α-Klotho reduced mouse

The deficiency of α-Klotho in mice causes phenotypes resembling human age-associated disorders at 3–4 weeks after birth and shows short lifespans of ∼2 months. One of the crucial symptoms is pulmonary emphysema, although α-Klotho is not expressed in the lungs. α-Klotho secreted from the kidneys is probably involved in the pathology of emphysema because kidney-specific knockout mice exhibit emphysematous structural changes. We examined whether any glycan changes in α-Klotho mouse lungs were observed, because α-Klotho is reported to have glycosidase activity. Here, we found the accumulation of heparan sulphate in the microsomal fraction of α-Klotho mouse lungs. Meanwhile, a disintegrin and metalloproteinase 17 (ADAM17) expression was decreased in α-Klotho mice. From these results, it is thought that the increase in heparan sulphate is due to insufficient cleavage of the core protein by ADAM17. Additionally, a reduction in α-Klotho and a decline of ADAM17 were also observed both in normal aged mice and in senescence marker protein-30 (SMP30) knockout mice, a mouse model of premature ageing. Thus, the decrease in ADAM17 is caused by the reduction in α-Klotho. These may be involved in the deterioration of lung function during ageing and may be associated with the pathology of pulmonary emphysema.

Monitoring hospital wastewaters for their probable genotoxicity

Hospitals' effluents contain a considerable amount of chemicals. Considering the significant volume of wastewater discharged by hospitals, the presence of these chemicals represents a real threat to the environment and human health. Thus, the aim of this study was to evaluate the in vivo and in vitro genotoxicities of three wastewater effluents collected from Tunisian hospitals. The liver of Swiss albino male mice, previously treated with different doses of the hospital wastewaters, was used as a model to detect DNA fragmentation. Our results showed all the hospital effluents caused significant qualitative and quantitative hazards in hepatic DNA. The wastewater collected from Sfax hospital exhibited the highest genotoxic effect, which may be explained by the presence in this effluent of some toxic micropolluants. There was a significant increase in genotoxicity, proportionally to the concentration of effluent. However, the vitotox assay did not show any significant genotoxicity on Salmonella typhimurium TA104 in the presence or absence of microsomal fraction S9. The ratio gentox/cytox was lower than the threshold 1.5. This study assessed the toxicological risk issued from Tunisian hospital wastewaters, which is potentially very harmful, and it has been pointed out that wastewater treatment requires special attention.

Diagnostic possibilities for autoimmune thyroiditis using non-invasive determination of intrathyroid iodine concentration in children

Sixty-seven children (55 girls and 12 boys) aged 5-16 years were examined. Autoimmune thyroiditis (AT) was diagnosed in 28 and diffuse nontoxic goiter (DNG) in 39. The diseases were diagnosed on the basis of case history, results of examination and palpation of the thyroid, ultrasonic findings, presence of antibodies to thyroglobulin (in AT) or their absence (in DNG), and the microsomal fraction detected by enzyme immunoassay using Boehringer Mannheim kits. AT diagnosis was confirmed cytomorphologically in all patients. Intrathyroid stable iodine (ISI) was measured by a Russian noninvasive x-ray fluorescent analyzer. ISI concentration was notably decreased in children with autoimmune thyroiditis confirmed by cytomorphological methods: below the threshold level of the method in 46%) cases and 120±10 mcg/g in 54%). This confirms a high informative value of the proposed method in this disease. Measurements of ISI in children with enlarged thyroid helps differentiate the hypertrophic form of AT from DNG: ISI concentration under 200 mcg/g is characteristic of AT, while in DNG the concentration of ISI in Moscow children is 500±40 mcg/g (M±m).