Inhibition of the metabolism of mutagens occurring in food by arachidonic acid

Ho, Ti; Coutts, T.M.; Rowland, Ian; Alldrick, A.J.

doi:10.1016/0027-5107(92)90210-s

Cited by 10 publications

(3 citation statements)

References 16 publications

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“…Currently, many presume that P450 is exclusively responsible for this reaction. However, the observations that linoleic acid, linolenic acid and arachidonic acid strongly inhibit the NADPH-dependent hepatic microsomal AFB 1 activation led investigators to a question whether P450 serves as the sole biocatalyst [143,144]. Thus, the identity and an assessment of contribution of other enzymes to AFB 1 activation are obviously important.…”

Section: Environmental Chemicalsmentioning

confidence: 99%

Role of Biotransformation in Conceptal Toxicity of Drugs and Other Chemicals

Kulkarni

2001

CPD

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Many developmental toxicants and teratogens require prior metabolism to reactive species or free radicals to exert toxicity. Thus the knowledge of conceptal biotransformation is absolutely critical in understanding toxicity of these chemicals. Due to extremely low content of cytochrome P450 in the embryo and other conceptal tissues, the research focus in recent years has steadily shifted toward enzymes capable of peroxidative oxidation of xenobiotics. At least three enzymes viz. lipoxygenase, peroxidase and prostaglandin synthase, each capable of peroxidative xenobiotic metabolism, occur in conceptal tissues of man and laboratory animals in biologically significant amounts. This review mainly summarizes the available information on the enzymatic bioactivation of teratogens and developmental toxicants belonging to diverse classes such as drugs, pesticides, environmental contaminants, industrial and other chemicals. Additionally, some discussion is devoted toward issues such as drug-drug interactions. The emerging new information on the peroxidative glutathione conjugate formation from xenobiotics is also presented. A critical need for gathering more information on this subject using different enzyme preparations from human conceptal tissues is stressed to avoid tragedies in the future.

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Section: Environmental Chemicalsmentioning

confidence: 99%

Role of Biotransformation in Conceptal Toxicity of Drugs and Other Chemicals

Kulkarni

2001

CPD

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“…The requisite event in AFB toxicity is its prior oxidation at the 8,9-vinyl ether bond to form the AFB-8,9-epoxide, an electrophilic species which is the ultimate carcinogenic metabolite. Linoleic acid, linolenic acid, and arachidonic acid strongly inhibit NADPH-dependent hepatic microsomal AFB activation [118,119]. This leads to a logical question as to whether P450 serves as the sole catalyst of this reaction.…”

Section: Xenobioticsmentioning

confidence: 99%

Lipoxygenase - a versatile biocatalyst for biotransformation of endobiotics and xenobiotics

Kulkarni¹

2001

CMLS, Cell. Mol. Life Sci.

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Lipoxygenase, a member of the arachidonate cascade enzymes, dioxygenates polyenoic fatty acids to finally yield products with profound and distinct biological activity. This review summarizes the available evidence for another role played by lipoxygenases in the metabolism of endobiotics and xenobiotics. Although other mechanisms exist, a direct hydrogen abstraction by the enzyme and the peroxyl radical-dependent chemical oxidation appear to be central to the co-oxidase activity of lipoxygenases. Besides polyunsaturated fatty acids, H2O2, fatty acid hydroperoxides, and synthetic organic hydroperoxides support the lipoxygenase-catalyzed xenobiotic oxidation. The major reactions documented thus far include oxidation, epoxidation, hydroxylation, sulfoxidation, desulfuration, dearylation, and N-dealkylation. It is noteworthy that lipoxygenases are also capable of glutathione conjugation of certain xenobiotics. The enzyme system appears to be inducible following exposure to chemicals. Lipoxygenases are inhibited by a large number of chemicals, some of which also serve as co-substrates. Available data suggest that lipoxygenases contribute to in vivo metabolism of xenobiotics in mammals.

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“…It is not a good substrate for cytochromes P450 (61). This view is further strengthened by several studies that have shown that low (micromolar) concentrations of polyunsaturated fatty acids significantly decrease the rate of NADPH-dependent cytochromes P450-catalyzed oxidation of xenobiotics in various liver preparations (62)(63)(64). This suppressive effect may be important in vivo since under normal physiological conditions, the tissue concentration of free arachidonate alone is 20 lM (60).…”

Section: Discussionmentioning

confidence: 83%