Effects of Nutritive Factors on Metabolic Processes Involving Bioactivation and Detoxication of Chemicals

Guengerich, F. Peter

doi:10.1146/annurev.nu.04.070184.001231

Cited by 57 publications

(9 citation statements)

References 82 publications

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“…Diet can have important effects on drug metabolism (Guengerich, 1984). The Africans were well nourished but their protein intake, particularly with regard to meat, was probably considerably less than that of the Caucasians.…”

Section: Discussionmentioning

confidence: 99%

Inter‐subject and ethnic differences in paracetamol metabolism.

Critchley¹,

Nimmo²,

Gregson³

et al. 1986

Brit J Clinical Pharma

134

104

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The 24 h urinary excretion of paracetamol and its metabolites following a single oral dose of 1.5 g was compared in 111 Caucasians (Scotland), 67 West Africans (Ghana) and 20 East Africans (Kenya). The fractional recovery of the mercapturic acid and cysteine conjugates of paracetamol was 9.3% in the Caucasians compared with only 5.2% and 4.4% in the Ghanaians and Kenyans respectively (P = less than 0.0005). This probably indicates markedly reduced metabolic activation of paracetamol in the Africans. There were no ethnic differences in the sulphate conjugation of paracetamol, but the mean fractional recovery of the glucuronide conjugate in Caucasians (54%) was significantly less than in the Africans (58%). The sulphate conjugation of paracetamol was increased and glucuronide conjugation reduced in Caucasian females compared with males. A similar trend was seen in the Ghanaians but there were no other significant sex differences. The range of intersubject variation in the metabolic activation of paracetamol was sixty fold compared with only a three fold variation in glucuronide and sulphate conjugation. This has important implications for susceptibility to paracetamol hepatotoxicity following overdosage especially in a small subgroup showing extensive metabolic activation. These ethnic differences in paracetamol metabolism may be related to genetic or environmental factors including differences in diet and protein intake.

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Section: Discussionmentioning

confidence: 99%

Inter‐subject and ethnic differences in paracetamol metabolism.

Critchley¹,

Nimmo²,

Gregson³

et al. 1986

Brit J Clinical Pharma

134

104

View full text Add to dashboard Cite

show abstract

“…Moderate protein deficiency (5% casein) has been shown to decrease a wide range of mixed-function oxidase reactions, including hydroxylation, oxidative dealkylation, and carcinogen epoxidation (36). On the other hand, a high-protein diet appears to enhance the rates of oxidative metabolism in humans (37). Our studies show that in the SLP group basal levels of cytochrome P-450, benzo[a]pyrene hydroxy-lase, and benzphetamine demethylase are about 50% of either the Std or SHP groups.…”

Section: Discussionmentioning

confidence: 65%

Modulations in the biotransformation of tobacco extract and N′‐nitrosonornicotine under differential dietary protein status

Ammigan

Nair

Amonkar

et al. 1989

J. Biochem. Toxicol.

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The modulation of the phase I and phase II biotransformation enzymes upon treatment with tobacco extract (TE) and N'-nitrosonornicotine (NNN) was investigated using male Sprague-Dawley rats fed differential protein diets. It was observed that the animals fed a low protein diet showed an overall decrease in the basal levels of hepatic and pulmonary phase I and II enzymes. TE and NNN significantly decreased the detoxifying system in the low-protein-fed animals. Animals fed 20% protein, however, showed significant increases in glutathione and glutathione S-transferase upon treatment. Furthermore, TE and NNN treatment brought about a significant depletion in the hepatic pool of vitamin A with a concomitant increase in the vitamin C levels.

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“…These dietary impacts can lead to changes in important enzyme levels and metabolism of environmental toxicants [28]. Long-term high sugar, high fat diets have been directly associated with decreased levels of AChE activity [29], with low protein diets more generally associated with lower enzyme production levels [30,31]. Decreased AChE activity due to diet could add to the percent inhibition occurring due to OP exposure.…”

Section: Methodsmentioning

confidence: 99%

Using Physiologically-Based Pharmacokinetic Models to Incorporate Chemical and Non-Chemical Stressors into Cumulative Risk Assessment: A Case Study of Pesticide Exposures

Wason¹,

Smith²,

Perry

et al. 2012

IJERPH

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Cumulative risk assessment has been proposed as an approach to evaluate the health risks associated with simultaneous exposure to multiple chemical and non-chemical stressors. Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models can allow for the inclusion and evaluation of multiple stressors, including non-chemical stressors, but studies have not leveraged PBPK/PD models to jointly consider these disparate exposures in a cumulative risk context. In this study, we focused on exposures to organophosphate (OP) pesticides for children in urban low-income environments, where these children would be simultaneously exposed to other pesticides (including pyrethroids) and non-chemical stressors that may modify the effects of these exposures (including diet). We developed a methodological framework to evaluate chemical and non-chemical stressor impacts on OPs, utilizing an existing PBPK/PD model for chlorpyrifos. We evaluated population-specific stressors that would influence OP doses or acetylcholinesterase (AChE) inhibition, the relevant PD outcome. We incorporated the impact of simultaneous exposure to pyrethroids and dietary factors on OP dose through the compartments of metabolism and PD outcome within the PBPK model, and simulated combinations of stressors across multiple exposure ranges and potential body weights. Our analyses demonstrated that both chemical and non-chemical stressors can influence the health implications of OP exposures, with up to 5-fold variability in AChE inhibition across combinations of stressor values for a given OP dose. We demonstrate an approach for modeling OP risks in the presence of other population-specific environmental stressors, providing insight about co-exposures and variability factors that most impact OP health risks and contribute to children’s cumulative health risk from pesticides. More generally, this framework can be used to inform cumulative risk assessment for any compound impacted by chemical and non-chemical stressors through metabolism or PD outcomes.

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Effects of Nutritive Factors on Metabolic Processes Involving Bioactivation and Detoxication of Chemicals

Cited by 57 publications

References 82 publications

Inter‐subject and ethnic differences in paracetamol metabolism.

Inter‐subject and ethnic differences in paracetamol metabolism.

Modulations in the biotransformation of tobacco extract and N′‐nitrosonornicotine under differential dietary protein status

Using Physiologically-Based Pharmacokinetic Models to Incorporate Chemical and Non-Chemical Stressors into Cumulative Risk Assessment: A Case Study of Pesticide Exposures

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