A correlation between cytotoxicity and reductase-mediated metabolism in cell lines treated with doxorubicin and daunorubicin.

The role of metabolism in daunorubicin (DAUN)- and doxorubicin (DOX)-associated toxicity in cancer patients is dependent on whether the parent drugs or major metabolites, doxorubicinol (DOXol) and daunorubicinol (DAUNol), are the more toxic species. Therefore, we examined whether an association exists between cytotoxicity and the metabolism of these drugs in cell lines from nine different tissues. Cytotoxicity studies using MTT [3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide] cell viability assays revealed that four cell lines [HepG2 (liver), HCT-15 (colon), NCI-H460 (lung), and A-498 (kidney)] were more tolerant to DAUN and DOX than the five remaining cell lines [H9c2 (heart), PC-3 (prostate), OVCAR-4 (ovary), PANC-1 (pancreas), and MCF-7 (breast)], based on significantly higher LC50 values at incubation times of 6, 24, and 48 hours.

Validation of a sequential extraction and liquid chromatography-tandem mass spectrometric method for determination of dihydrotestosterone, androstanediol and androstanediol-glucuronide in prostate tissues.

Androgens are key mediators of prostate development and function, a role that extends to the development of prostate diseases such as benign prostatic hyperplasia (BPH) and prostate cancer. In prostate, DHT is the major androgen and reduction and glucuronidation are the major metabolic pathways for DHT elimination. A streamlined method for quantitation of dihydrotestosterone (DHT), 5α-androstan-3α,17β-diol (3α-diol), and 3α-diol glucuronide (diol-gluc) was established and validated for use with archived prostate tissue specimens to facilitate examination of the roles of the underlying metabolism.

Naturally occurring variants of human aldo-keto reductases with reduced in vitro metabolism of daunorubicin and doxorubicin.

Doxorubicin (DOX) and daunorubicin (DAUN) are effective anticancer drugs; however, considerable interpatient variability exists in their pharmacokinetics. This may be caused by altered metabolism by nonsynonymous single-nucleotide polymorphisms (ns-SNPs) in genes encoding aldo-keto reductases (AKRs) and carbonyl reductases. This study examined the effect of 27 ns-SNPs, in eight human genes, on the in vitro metabolism of both drugs to their major metabolites, doxorubicinol and daunorubicinol.

Naturally occurring variants of human CBR3 alter anthracycline in vitro metabolism.

Doxorubicin (DOX) and daunorubicin (DAUN) are anthracycline anticancer agents; however, considerable interpatient variability exists in their pharmacokinetics. This interpatient variability is attributed in part to altered metabolism by nonsynonymous single-nucleotide polymorphisms (ns-SNPs) in genes encoding the carbonyl reductases. This study examines the effect of seven naturally occurring ns-SNPs in the CBR3 gene on in vitro metabolism of anthracyclines to doxorubicinol and daunorubicinol.

Two nonsynonymous single nucleotide polymorphisms of human carbonyl reductase 1 demonstrate reduced in vitro metabolism of daunorubicin and doxorubicin.

Carbonyl reductases (CBRs) are a group of metabolic enzymes belonging to the short-chain dehydrogenase family with NADPH-dependent oxidoreductase activity. These enzymes are known to metabolize the anthracyclines doxorubicin (DOX) and daunorubicin (DAUN). Both DOX and DAUN are highly effective in cancer therapy; however, there is considerable interpatient variability in adverse effects seen in patients undergoing treatment with these drugs.

Functional and energetic characterization of P-gp-mediated doxorubicin transport in rainbow trout (Oncorhynchus mykiss) hepatocytes.

An assessment of energetic costs associated with P-glycoprotein (P-gp)-mediated xenobiotic efflux is important in understanding the energy budgets, tradeoffs, and fitness of organisms inhabiting contaminated environments. Here, a functional characterization and determination of the energetic costs associated with doxorubicin (DOX) efflux was examined in isolated hepatocytes of rainbow trout. The accumulation and efflux of DOX were both concentration dependent.

Aldo-keto reductase 1C2 fails to metabolize doxorubicin and daunorubicin in vitro.

The anthracycline drugs are important for the treatment of a number of malignancies; however, their clinical use is associated with dose-dependent severe chronic cardiotoxicity. Although the mechanism for this side effect has not yet been identified, the alcohol metabolites formed during daunorubicin (DAUN) and doxorubicin (DOX) therapies have been implicated. The alcohol metabolites of DAUN and DOX, daunorubicinol (DAUNol) and doxorubicinol (DOXol), respectively, are generated through reduction of the C-13 carbonyl function, which is reportedly mediated by members of the aldo-keto reductase and carbonyl reductase families of proteins.

Two allelic variants of aldo-keto reductase 1A1 exhibit reduced in vitro metabolism of daunorubicin.

Aldo-keto reductases (AKRs) are a class of NADPH-dependent oxidoreductases that have been linked to metabolism of the anthracyclines doxorubicin (DOX) and daunorubicin (DAUN). Although widely used, cardiotoxicity continues to be a serious side effect that may be linked to metabolites or reactive intermediates generated in their metabolism. In this study we examine the little known effects of nonsynonymous single nucleotide polymorphisms of human AKR1A1 on the metabolism of these drugs to their alcohol metabolites.

Cadmium chloride-induced disruption of testicular steroidogenesis in rainbow trout, Oncorhynchus mykiss.

Cadmium (Cd) is a known endocrine disruptor with the ability to affect the production of hormones involved in the regulation of reproductive processes. In the present study, the effects of CdCl(2) on unstimulated and stimulated testicular steroidogenesis were examined with the intention of furthering the understanding of the potential site(s) of action in the signaling pathway for 11-KT synthesis in teleosts. In short-term (2-h) exposures, CdCl(2 )stimulated 11-KT production (29% and 28% over controls) in minced testicular tissues at concentrations of 10 and 100 microM, respectively.

Biosynthetic capacity of rainbow trout (Oncorhynchus mykiss) interrenal tissue after cadmium exposure.

The disruption of endocrine system function in wildlife species, including teleosts, by contaminants such as metals is presently of major environmental concern. Recently, it has been shown that cadmium (Cd) exposure results in significant reductions in corticosteroid secretion by fish interrenal steroidogenic cells, likely through an inhibition of intracellular cortisol synthesis. In the present study, the effects of CdCl(2) on unstimulated and stimulated interrenal steroidogenesis in rainbow trout were examined with the intention of furthering an understanding of the site(s) of Cd toxic action.

Alterations in respiration rate of isolated rainbow trout hepatocytes exposed to the P-glycoprotein substrate rhodamine 123.

Reducing intracellular xenobiotic concentration is an important defence strategy used by cells challenged with foreign chemicals. One mechanism used to achieve this goal is via the use of P-glycoproteins (P-gps), ATP-dependent transporters that mediate the removal of hydrophobic compounds from cells. The energetic costs of this mechanism are unknown, therefore, the activity and respiratory costs associated with the P-gp-mediated efflux of rhodamine 123 (R123) was measured in isolated rainbow trout hepatocytes.

Energetic costs of pyrene metabolism in isolated hepatocytes of rainbow trout, Oncorhynchus mykiss.

The respiratory costs of pyrene exposure and biotransformation were examined in isolated hepatocytes of adult rainbow trout, Oncorhynchus mykiss. Baseline oxygen consumption rates measured at an acclimation temperature of 7.5 degrees C and during an acute temperature increase to 15 degrees C were 10.