cyadox and quindoxin

Quinoxaline 1,4-dioxide derivatives (QdNOs) with a wide range of biological activities are used in animal husbandry worldwide. It was found that QdNOs significantly inhibited the gene expression of CYP11B1 and CYP11B2, the key aldosterone synthases, and thus reduced aldosterone levels. However, whether the metabolites of QdNOs have potential adrenal toxicity and the role of oxidative stress in the adrenal toxicity of QdNOs remains unclear. The relatively new QdNOs, cyadox (CYA), mequindox (MEQ), quinocetone (QCT) and their metabolites, were selected for elucidation of their toxic mechanisms in H295R cells. Interestingly, the results showed that the main toxic metabolites of QCT, MEQ, and CYA were their N1-desoxy metabolites, which were more harmful than other metabolites and evoked dose and time-dependent cell damage on adrenal cells and inhibited aldosterone production. Gene and protein expression of CYP11B1 and CYP11B2 and mRNA expression of transcription factors, such as NURR1, NGFIB, CREB, SF-1, and ATF-1, were down regulated by N1-desoxy QdNOs. The natural inhibitors of oxidant stress, oligomeric proanthocyanidins (OPC), could upregulate the expression of diverse transcription factors, including CYP11B1 and CYP11B2, and elevated aldosterone levels to reduce adrenal toxicity. This study demonstrated for the first time that N1-desoxy QdNOs have the potential to be the major toxic metabolites in adrenal toxicity, which may shed new light on the adrenal toxicity of these fascinating compounds and help to provide a basic foundation for the formulation of safety controls for animal products and the design of new QdNOs with less harmful effects.

Topics: Adrenal Gland Diseases; Aldosterone; Antioxidants; Biotransformation; Cell Line; Cell Survival; Cytochrome P-450 CYP11B2; Humans; Oxidative Stress; Proanthocyanidins; Quinoxalines; RNA, Messenger; Steroid 11-beta-Hydroxylase

Quindoxin (quinoxaline-1,4-dioxide), a former 'growth promoter' used in animal husbandry, has been taken from the market because of its photoallergic properties. Nowadays its derivatives olaquindox, carbadox and cyadox are frequently applied for the same purpose. Recent reports show that olaquindox too, can induce photoallergic skin reactions in stockmen. From the present investigation it appeared that all compounds mentioned, form a reactive oxaziridine upon exposure to light, just like many other imino-N-oxides. Photoreactivity with protein, which is considered as an important condition for a compound to be a potential photoallergen, was also studied. Quindoxin and olaquindox proved to meet this condition, as was expected. But carbadox and cyadox also react and were shown to be even more reactive towards human serum albumin.

Topics: Animals; Anti-Bacterial Agents; Carbadox; Chemical Phenomena; Chemistry; Humans; Organophosphorus Compounds; Photochemistry; Photosensitivity Disorders; Proteins; Quinoxalines; Serum Albumin; Ultraviolet Rays

The cytogenetic activities of 3 growth-promoting agents carbadox, olaquindox and cyadox were examined by the micronucleus test. These chemicals were administered i.p. to male Wistar rats 30 and 6 h before they were killed. Single-dose levels were 5, 10, 15, 30, 60, 90, 120 and 240 mg/kg for carbadox; 30, 60, 90, 120 and 240 mg/kg for olaquindox; and for cyadox 30, 60, 120 and 240 mg/kg. Over the entire dose range tested, carbadox induced a statistically significant increase in the number of micronucleated polychromatic erythrocytes in the rat bone marrow, whereas similar activity of olaquindox started at a dose of 2 X 60 mg/kg. The effect of cyadox was very low even at the highest dosage tested. Further testing of the genotoxicity of this class of chemicals is required. The genetic activity of the solvent used (dimethyl sulfoxide) is briefly discussed.

Topics: Animals; Anti-Bacterial Agents; Bone Marrow; Carbadox; Cell Nucleus; Erythrocytes; Male; Mutagenicity Tests; Mutagens; Mutation; Quinoxalines; Rats; Rats, Inbred Strains; Structure-Activity Relationship