Stereochemistry of the Biotransformation of 1-Hexene and 2-Methyl-1-hexene with Rat Liver Microsomes and Purified P450s of Rats and Humans

Abstract

The epoxidation of 1-hexene (1a) and 2-methyl-1-hexene (1b), two hydrocarbons present in the ambient air as pollutants, is catalyzed by some human and rat P450 enzymes. The enantioselectivities of these processes, when the reactions were carried out using rat and human liver microsomal preparations, were modest and dependent on both P450 composition and substrate concentrations. Various P450 isoforms (rat P450 2B1 and human P450 2C10 and 2A6) catalyzed the double bond oxidation of 1a and 1b with different product enantioselectivities. In the case of 1a, a moderately enantioselective hydroxylation at the allylic C(3) with the formation of 1-hexen-3-ol (4a) by microsomes from control or preinduced rats was also observed. The oxidation of this metabolite was, in turn, catalyzed by rat liver microsomes and mainly by rat P450 2C11, leading exclusively to the formation of 1-hexen-3-one, with no double bond epoxidation being observed. The stereochemical course of the microsomal epoxide hydrolase-catalyzed hydrolysis of the epoxy alcohols, threo-(+/-)- and erythro-(+/-)-1, 2-epoxyhexan-3-ol, theoretically expected to be formed from 4a, has been investigated.

Opinion of the Scientific Panel on food additives, flavourings, processing aids and materials in contact with food (AFC) related to Flavouring Group Evaluation 6 (FGE.06): Straight-and branched-chain aliphatic unsatured primary alcohols, aldehydes, carbox

“…It has been demonstrated that terminal double bonds may be oxidatised at the double bond to give the corresponding epoxide or, alternatively, at the allylic carbon to give the allylic alcohol, as was demonstrated with 1-hexene with rat and human P450s (Chiappe et al, 1998). The ratio of epoxidation over allylic oxidation, as measured with different P450 isoforms (CYP) is ≥1, indicating that epoxide formation is generally favoured (Chiappe et al, 1998).…”

“…The ratio of epoxidation over allylic oxidation, as measured with different P450 isoforms (CYP) is ≥1, indicating that epoxide formation is generally favoured (Chiappe et al, 1998). Theoretically these pathways could occur with the candidate substances 02.175,02.201,06.143,and 05.174].…”

Flavouring Group Evaluation 7, Revision 2 (FGE.07Rev2) : Saturated and unsaturated aliphatic secondary alcohols, ketones and esters of secondary alcohols and saturated linear or branched-chain carboxylic acids from chemical group 5

“…1-Alkenes are metabolised by P450 through both double bond oxidation to the corresponding epoxide and allylic oxidation (Chiappe et al, 1998). The rates of the two reactions measured with different P450 isoforms indicate that epoxide formation is generally favoured (Chiappe et al, 1998). Therefore, due to the similar position of the double bond, it cannot be ruled out that, in addition to the above mentioned metabolic pathways for ketones, the three candidate substances 07.201 and 07.239] may be, at least partially, biotransformed to an epoxide.…”

“…The latter two reactions can be considered to be detoxications. 1-Alkenes are metabolised by P450, through both double bond oxidation to the corresponding epoxide and allylic oxidation (Chiappe et al, 1998). The rates of the two reactions measured with different P450 isoforms indicate that epoxide formation is generally favoured (Chiappe et al, 1998).…”

Flavouring Group Evaluation 25, (FGE.25) - Aliphatic and aromatic hydrocarbons from chemical group 31 - Scientific Opinion of the Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food

“…Due to the large strain associated with the three membered ring structure epoxides easily react with nucleophilic sites of cellular macromolecules; conversely they are readily detoxified either spontaneously or by the action of epoxide hydrolase to diols or conjugated with reduced glutathione by glutathione-S-transferases. 1-Alkenes are metabolised by cytochrome P450, through double bond oxidation to the corresponding epoxide or alternatively allylic oxidation (Chiappe et al, 1998). The rates of the two reactions measured with different cytochrome P450 isoforms indicate that epoxide formation is generally favoured (Chiappe et al, 1998) and this may also apply in particular to the candidate substance dodec-1-ene ].…”