A physiologically based in silico model for trans-2-hexenal detoxification and DNA adduct formation in human including interindividual variation indicates efficient detoxification and a negligible genotoxicity risk

Abstract

A number of α,β-unsaturated aldehydes are present in food both as natural constituents and as flavouring agents. Their reaction with DNA due to their electrophilic α,β-unsaturated aldehyde moiety may result in genotoxicity as observed in some in vitro models, thereby raising a safety concern. A question that remains is whether in vivo detoxification would be efficient enough to prevent DNA adduct formation and genotoxicity. In this study, a human physiologically based kinetic/dynamic (PBK/D) model of trans-2-hexenal (2-hexenal), a selected model α,β-unsaturated aldehyde, was developed to examine dose-dependent detoxification and DNA adduct formation in humans upon dietary exposure. The kinetic model parameters for detoxification were quantified using relevant pooled human tissue fractions as well as tissue fractions from 11 different individual subjects. In addition, a Monte Carlo simulation was performed so that the impact of interindividual variation in 2-hexenal detoxification on the DNA adduct formation in the population as a whole could be examined. The PBK/D model revealed that DNA adduct formation due to 2-hexenal exposure was 0.039 adducts/10⁸ nucleotides (nt) at the estimated average 2-hexenal dietary intake (0.04 mg 2-hexenal/kg bw) and 0.18 adducts/10⁸ nt at the 95th percentile of the dietary intake (0.178 mg 2-hexenal/kg bw) in the most sensitive people. These levels are three orders of magnitude lower than natural background DNA adduct levels that have been reported in disease-free humans (6.8-110 adducts/10⁸ nt), suggesting that the genotoxicity risk for the human population at realistic dietary daily intakes of 2-hexenal may be negligible.

An integrated QSAR-PBK/D modelling approach for predicting detoxification and DNA adduct formation of 18 acyclic food-borne α,β-unsaturated aldehydes

“…The PBK/D models for trans-2-hexenal for rat and human revealed that DNA adduct formation in the liver due to intake of trans-2-hexenal at human dietary exposure levels would be three to six orders of magnitude lower than the natural background levels of structurally similar 1,N 2 -exocyclic deoxyguanosine adducts in disease free human liver. Based on this observation we concluded that at realistic dietary exposure levels the DNA adduct formation may be negligible (Kiwamoto et al, 2012;Kiwamoto et al, 2013). trans-2-Hexenal is, however, only one of the many α,β-unsaturated aldehydes present in diet and it remains unknown whether the results would be similar for other acyclic α,β-unsaturated aldehydes.…”

“…c o m / l o c a t e / y t a a p detoxification is indeed sufficient to prevent significant DNA adduct formation of acyclic α,β-unsaturated aldehydes in vivo. Using trans-2-hexenal as model compound, we have previously shown that physiologically based kinetic/dynamic (PBK/D) modelling gives insights in detoxification and DNA adduct formation of α,β-unsaturated aldehydes in vivo (Kiwamoto et al, 2012;Kiwamoto et al, 2013). The PBK/D models for trans-2-hexenal for rat and human revealed that DNA adduct formation in the liver due to intake of trans-2-hexenal at human dietary exposure levels would be three to six orders of magnitude lower than the natural background levels of structurally similar 1,N 2 -exocyclic deoxyguanosine adducts in disease free human liver.…”

“…The V max values expressed as nmol/min/(mg S9 protein) and k values expressed as ml/min/(mg S9 protein) were scaled to be expressed as nmol/min/(g tissue) and ml/min/(g tissue) respectively, using S9 protein yields of 143 mg/g liver or 11.4 mg/g small intestine as scaling factors (van de Kerkhof et al, 2007;Punt et al, 2009;Kiwamoto et al, 2012). Chemical conjugation of the aldehydes with GSH or protein reactive sites in the liver or small intestine was described as previously reported (Kiwamoto et al, 2012;Kiwamoto et al, 2013). Equations to describe GSH levels in the liver and small intestine were included as previously described (Kiwamoto et al, 2012) to examine possible depletion of GSH induced by the dietary aldehydes.…”

Scientific Opinion on Flavouring Group Evaluation 200 (FGE.200): 74 α,β‐unsaturated aldehydes and precursors from subgroup 1.1.1 of FGE.19

“…Thus, dietary exposure to doses that do not deplete glutathione, and therefore do not lead either to tissue damage or DNA adducts would not be expected to pose a mutagenic or carcinogenic hazard (Kiwamoto et al, 2012(Kiwamoto et al, , 2013. However, the Panel considered that PBK/D studies are not sufficient due to the lack of validation.…”

“…The PBK/D model predicts that hex-2(trans)-enal is readily detoxified through glutathione conjugation at 30 mg/kg bw and below. The same model was further developed to examine dose-dependent detoxification and DNA adducts formation in humans upon dietary exposure (Kiwamoto et al, 2013). In this study the kinetic parameters were derived from literature or calculated through in vitro reactions using human tissue fractions, taking into account interindividual differences.…”