Paclitaxel is an important, recently introduced anti-neoplastic drug. Paclitaxel metabolites are virtually inactive in comparison with the parent drug. The study investigated whether phenolic antioxidants could inhibit metabolic inactivation sufficiently to increase paclitaxel effects. Cytochrome p450 (CYP)-catalysed metabolism of paclitaxel was investigated in rat and human liver microsomes. In rat microsomes, paclitaxel was metabolised mainly to C3'-hydroxypaclitaxel (C3'-OHP), less to C2-hydroxypaclitaxel (C2-OHP), di-hydroxypaclitaxel (di-OHP) and another monohydroxylated paclitaxel. In human liver microsomes, 6alpha-hydroxypaclitaxel (6alpha-OHP), formed by CYP2C8, was the main metabolite, while C3'-OHP, C2-OHP and another product different from di-OHP were minor metabolites, formed by CYP3A4. In individual human livers 6alpha-OHP was formed at 1.8-fold to 13-fold higher rates than C3'-OHP. Kinetic parameters (K(m) and V(max)) of production of various metabolites in rat and human liver microsomes revealed differences between species as well as human individual differences. Nine phenolic antioxidants ((+)-catechin, (-)-epicatechin, fisetin, gallic acid, morin, myricetin, naringenin, quercetin and resveratrol) were tested for inhibition of paclitaxel metabolism. In rat microsomes, resveratrol was more inhibitory than fisetin; the other phenolic antioxidants were without effect. In human microsomes, the inhibiting potency decreased in the order fisetin >quercetin >morin >resveratrol, while the other phenolic antioxidants were not inhibitory; the formation of 6alpha-OHP (CYP2C8) was generally more inhibited than that of C3'-OHP. The inhibition was mostly mixed-type. The results suggest that oral administration of some phenolic substances might increase paclitaxel blood concentrations during chemotherapy.

• MeSH
• Drug Antagonism MeSH
• Antioxidants pharmacology   MeSH
• Aryl Hydrocarbon Hydroxylases antagonists & inhibitors   metabolism   MeSH
• Cytochrome P-450 CYP3A MeSH
• Cytochrome P-450 CYP2C8 MeSH
• Adult MeSH
• Species Specificity MeSH
• Phenols pharmacology   MeSH
• Antineoplastic Agents, Phytogenic antagonists & inhibitors   chemistry   metabolism   MeSH
• Microsomes, Liver enzymology   metabolism   MeSH
• Rats MeSH
• Humans MeSH
• Adolescent MeSH
• Oxidoreductases, N-Demethylating antagonists & inhibitors   metabolism   MeSH
• Paclitaxel antagonists & inhibitors   chemistry   metabolism   MeSH
• Rats, Wistar MeSH
• In Vitro Techniques MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Adult MeSH
• Rats MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• Antioxidants MeSH
• Aryl Hydrocarbon Hydroxylases MeSH
• CYP2C8 protein, human MeSH Browser
• Cytochrome P-450 CYP3A MeSH
• Cytochrome P-450 CYP2C8 MeSH
• Phenols MeSH
• Antineoplastic Agents, Phytogenic MeSH
• Oxidoreductases, N-Demethylating MeSH
• Paclitaxel MeSH

Cytochrome P450 (CYP) 2E1 was the most efficient CYP enzyme that oxidized benzene to soluble and covalently bound metabolites in rat and human liver microsomes. The covalent binding was due mostly to the formation of benzoquinone (BQ), the oxidation product of hydroquinone (HQ), and was inversely related to the formation of soluble metabolites. In rats, inhalation of benzene (4 mg/liter of air) caused a rapid destruction of CYP2B1 previously induced by phenobarbital. The ability of benzene metabolites to destroy liver microsomal CYP in vitro decreased in the order BQ > HQ > catechol > phenol. The destruction was reversed by ascorbate and diminished by alpha-tocopherol, suggesting that HQ was not toxic, whereas BQ and semiquinone radical (SQ) caused the effect. In the presence of nicotinamide adenine dinucleotide phosphate, reduced (NADPH) the microsomes did not oxidize HQ to BQ, while the formation of superoxide anion radical from both HQ and BQ was markedly quenched. Destruction of CYP in vitro caused by HQ or BQ was not mediated by hydroxyl radical formation or by lipid peroxidation. On the contrary, HQ and BQ inhibited NADPH-mediated lipid peroxidation. Ascorbate induced high levels of hydroxyl radical formation and lipid peroxidation, which were differentially affected by quinones, indicating different mechanisms. Despite reducing the toxicity of HQ and BQ, ascorbate appeared to induce its own toxicity, reflected in high levels of lipid peroxidation. Iron redox cycling played a significant role in the NADPH-induced hydroxyl radical formation but not in that caused by ascorbate; however, lipid peroxidation induced by NADPH or ascorbate was suppressed by ethylenediaminetraacetate, indicating a crucial role of iron. Thus, the data indicate that the quinones destroyed CYP directly and not via oxygen activation or lipid peroxidation.

• MeSH
• DNA Adducts biosynthesis   MeSH
• Benzene metabolism   toxicity   MeSH
• Benzoquinones metabolism   toxicity   MeSH
• Cytochrome P-450 CYP2E1 metabolism   MeSH
• Hydroquinones metabolism   toxicity   MeSH
• Microsomes, Liver metabolism   MeSH
• Rats MeSH
• Humans MeSH
• Oxidation-Reduction MeSH
• DNA Damage MeSH
• Rats, Wistar MeSH
• Proteins drug effects   metabolism   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Cytochrome P-450 Enzyme System metabolism   MeSH
• In Vitro Techniques MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• DNA Adducts MeSH
• Benzene MeSH
• Benzoquinones MeSH
• Cytochrome P-450 CYP2E1 MeSH
• Hydroquinones MeSH
• hydroquinone MeSH Browser
• Proteins MeSH
• quinone MeSH Browser
• Reactive Oxygen Species MeSH
• Cytochrome P-450 Enzyme System MeSH