Differences in metabolism of the marine biotoxin okadaic acid by human and rat cytochrome P450 monooxygenases

Abstract

The ingestion of seafood contaminated with the marine biotoxin okadaic acid (OA) can lead to diarrhetic shellfish poisoning with symptoms like nausea, vomiting and abdominal cramps. Both rat and the human hepatic cytochrome P450 monooxygenases (CYP) metabolize OA. However, liver cell toxicity of metabolized OA is mainly unclear. The aim of our study was to detect the cellular effects in HepG2 cells exposed to OA in the presence of recombinant CYP enzymes of both rat and human for the investigation of species differences. The results should be set in correlation with a CYP-specific metabolite pattern. Comparative metabolite profiles of OA after incubation in rat and human recombinant CYP enzymes were established by using LC-MS/MS technique. Results demonstrated that metabolism of OA to oxygenated metabolites correlates with detoxification which was mainly catalyzed by human CYP3A4 and CYP3A5. Detoxification by rat Cyp3a1 was lower compared to human CYP3A enzymes and activation of OA by Cyp3a2 was observed, coincident with minor overall conversion capacity of OA. By contrast human and rat CYP1A2 seem to activate OA into cytotoxic intermediates. In conclusion, different mechanisms of OA metabolism may occur in the liver. At low OA doses, the human liver is likely well protected against cytotoxic OA, but for high shellfish consumers a potential risk cannot be excluded.

Integrated Array Chip for High-Throughput Screening of Species Differences in Metabolism

“…Moreover, the metabolism-induced anticancer bioactivities upon administration of CAP and CPT-11 were independent of NADPH, whereas the NADPH-deficient co-culture system showed no inhibition on cell viabilities with the treatment of CTX and FT (Figure e). The results verified that NADPH-dependent CYP450 enzymes metabolize the CTX and FT, whereas the CES enzyme catalyzing the CAP and CPT-11 is independent of NAPDH. , …”

Evaluation of the inhibition potential of plumbagin against cytochrome P450 using LC-MS/MS and cocktail approach

“…In fact, metabolic activation was achieved by incubation of plumbagin in the presence of CYP3A2 when the concentrations of midazolam are less than 5 μΜ in RLMs41. In this report, however, the unusual effects of plumbagin on CYP3A2 could be explained using an atypical kinetics model.…”

“…As mentioned above, when investigating the enzyme inhibition kinetic of CYP3A2, we found it did not conform to the classical Michaelis–Menten kinetics in RLMs. In fact, metabolic activation was achieved by incubation of plumbagin in the presence of CYP3A2 when the concentrations of midazolam are less than 5 μΜ in RLMs 41 . In this report, however, the unusual effects of plumbagin on CYP3A2 could be explained using an atypical kinetics model.…”

Cinnamaldehyde Could Reduce the Accumulation of Diarrhetic Shellfish Toxins in the Digestive Gland of the Mussel Perna viridis under Laboratory Conditions

“…Detoxification of bivalve molluscs is a complex process concerning cytochromes P450 and other enzymes and transporters. Studies have shown that CYP3A, such as CYP3A4 and CYP3A1, were involved in the metabolism and detoxification of DSTs in mammalian cell lines [25][26][27]. Recently, based on the finding that the content of DSTs was significantly decreased in mussels when the activity of CYP3A4 was inhibited by ketoconazole, Wei et al proposed that CYP3A4 might play an important role in DST metabolism in bivalves.…”