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Journal of Ethnopharmacology 87 (2003) 3–9

Effect of Catha edulis (khat) chewing on plasma lipid peroxidation


A. Al-Zubairi, M. Al-Habori∗ , A. Al-Geiry
Department of Clinical Biochemistry, Faculty of Medicine and Health Sciences, University of Sanaa, Sanaa, Yemen
Received 24 May 2002; received in revised form 14 November 2002; accepted 14 March 2003

Abstract

The effect of regular khat (Catha edulis) chewing and the combination of khat chewing and smoking on plasma lipid peroxidation as a
biomarker of oxidative stress and free radical activity (measured as plasma malondialdehyde, MDA), as well as on the lipid profiles were
investigated. The fasting plasma levels of MDA were non-significantly higher in both groups (4% in khat chewers and 9.2% in khat chewers
and smokers), whereas these levels were observed to be significantly increased at post meal and 2 h through the khat session. Post meal increase
of plasma MDA could be attributed partially to the meal-induced oxidative stress and the possible decrease in the overall antioxidant capacity.
This increase in plasma levels of MDA in both tested groups were found to be higher in the control group suggesting the presence of other
contributing factors beside the meal-induced oxidative stress. Plasma levels of MDA were observed to fall slightly 2 h through the khat session
over the post meal levels, suggesting a lack of additive effect of khat consumption. Plasma triglycerides, total cholesterol, and LDL-cholesterol
were shown to be non-significantly affected in this study by khat chewing or by the combination of khat chewing and smoking.
© 2003 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Catha edulis; Khat; Lipid peroxidation; Plasma lipid profile

1. Introduction enzymes and increase non-specific permeability to ions such


as calcium ions. Moreover, cellular oxidants can target DNA
It has been suggested, in the pathogenesis of many in the cell, and initiation of ROS with DNA appears to affect
diseases and toxicity’s of numerous chemicals, the partic- the regulation of certain genes (Cerutti and Trump, 1991;
ipation of radicals and oxidants (Kehrer, 1993). The most Harris, 1992). These interactions may involve direct modi-
common oxidants are the superoxide and hydroxyl radicals fications of DNA or they may be mediated through changes
and hydrogen peroxide which are referred to as reactive in transcription factors or enzymes involved in regulating
oxygen species (ROS) (Halliwell and Gutteridge, 1989; gene expression (Esterbauer et al., 1990; Cao et al., 1995).
Sies, 1991; Halliwell, 1996). Superoxide radical can induce The habit of khat chewing has prevailed for centuries
important reducing reactions in biological material and its among populations in the horn of east Africa and the Arabian
formation leads to a cascade of other ROS (Grisham, 1992; peninsula including The Yemen. Fresh leaves of khat (Catha
Moslen, 1994). Lipids, proteins, and DNA are all capable of edulis Forsk) are customarily chewed to attain a state of
reacting with radicals and oxidants. Lipids have been exten- stimulation (Kalix, 1984; Al-Meshal et al., 1985; Al-Bekairi
sively studied because of their critical, structural, and func- et al., 1991). Although the use of khat is widespread, it
tional role in membranes and because of the relative ease has until recently remained mostly confined to the regions
with which products of lipid peroxidation can be measured where the plant is grown since only fresh leaves have the
(Gutteridge, 1988). Polyunsaturated fatty acids (PUFA) potency (of cathinone) to produce the desired effects. The
are particularly susceptible to peroxidation and that, once fact that cathinone has a closer structural similarity with
initiated the process proceeds as a free radical chain reac- amphetamine, and both share common pharmacodynamic
tion (Gutteridge and Halliwell, 1990). Lipid peroxidation features, led to the conclusion that cathinone is the most
of biological membranes causes impairment of membrane important active ingredient of khat which causes the major
function (Gutteridge, 1988; Halliwell and Gutteridge, 1989) pharmacological effects (Hollister, 1995).
decreased fluidity, inactivate membrane bound receptors and The common adverse effects of khat include insomnia,
anorexia, hyperthermia, mydriasis, and endocrinological
∗ Corresponding author. Tel.: +967-1-440-910; fax: +967-1-440-842. disturbances (Nencini et al., 1983; Brenneisen et al., 1990).
E-mail address: malhabori@hotmail.com (M. Al-Habori). The detrimental effects of the active principle of khat on

0378-8741/03/$ – see front matter © 2003 Elsevier Science Ireland Ltd. All rights reserved.
doi:10.1016/S0378-8741(03)00101-6
4 A. Al-Zubairi et al. / Journal of Ethnopharmacology 87 (2003) 3–9

man and animals have been described by Kalix and Khan (EDTA) (Wong et al., 1987) and were used for the measure-
(1984). Khat-induced analgesia has been reported (Connor ment of lipid peroxidation products (lipid peroxidation assay
et al., 2000), although it is not known whether the mech- kit, Oxford, USA). The malondialdehyde (MDA) estima-
anism is central or peripheral. Acute autonomic responses, tion was based on the reaction of MDA with two molecules
such as elevated blood pressure and tachycardia, have been of N-methyl-2-phenylindole to give a colored complex. The
reported (Duke, 1985; Widler et al., 1994). Clinical trial second tube were plain and were used for the analysis of lipid
have shown khat to delay gastric emptying period after khat profiles (cholesterol, triglycerides, HDL-cholesterol assay
chewing (Heymann et al., 1995). kits, Randox Labs, UK). LDL-cholesterol were calculated
Although investigations into the khat effects have spanned using the Friedewald equation (Friedewald et al., 1972):
various physiological and metabolic effects, none has yet
investigated the effects of khat chewing on lipid peroxi- LDL-cholesterol  
dation/free radical generation. The aim of this study was, HDL-cholesterol + TG
= total cholesterol −
therefore, to investigate the effect of regular khat chew- 5
ing and the combination of khat chewing and smoking on
plasma lipid peroxidation and that of the lipid profile in 2.1. Statistical analysis
healthy Yemeni individuals.
Samples were measured in duplicates and were expressed
as means ± S.D. Statistical analysis was carried out by Epi
2. Materials and methods Info version-6 (EPI6), for windows. One-way ANOVA was
used to test the statistical significance between two indepen-
In this study, 107 Yemeni male subjects aged 20–45 years dent groups.
old (mean age 29) with a Body Mass Index of 17–25 kg/m2
were randomly selected and divided into three main groups:
the first group included 40 individuals that were classified 3. Results
as khat chewers on daily basis (>2 years) without smok-
ing, the second group included 40 individuals that were Table 1 shows the fasting plasma levels of MDA and lipid
classified as khat chewers on daily basis and smokers of profile in both khat chewers and khat chewers and smokers.
at least 10 cigarettes per day, and the third group included The fasting plasma MDA was non-significantly higher by 3.9
27 individuals classified as non-khat chewers, non-smokers and 9.2% in khat chewers and khat chewers and smokers, re-
(control group). All the subjects in the above groups were spectively, with respect to the control group. Along the same
subjected to a standard meal (lunch) of equal lipid contents. line, fasting plasma triglycerides non-significantly higher by
Three blood samples were collected from each individual 9 and 13% in khat chewers and khat chewers and smokers,
(after an overnight fast, post meal—after lunch, and after respectively. In contrast, fasting total plasma cholesterol
2 h through the khat session, respectively). Collected blood non-significantly lower by approximately 10 and 13% in
were divided into two tubes, the first tube were with antico- khat chewers and khat chewers and smokers, respectively.
agulant ethylene diamine tetra acetic acid-dipotassium salt Similarly, the calculated fasting plasma LDL-cholesterol

Table 1
Fasting plasma levels of MDA and lipid profile in both khat chewers and khat chewers and smokers
Control Khat chewers Khat chewers and smokers

Malondialdehyde (␮mol/l) 0.508 ± 0.101 0.528 ± 0.510 0.555 ± 0.185


Triglycerides (mg/dl) 85.15 ± 36.73 92.77 ± 49.26 96.00 ± 55.80
Total cholesterol (mg/dl) 146.58 ± 37.53 132.60 ± 43.40 127.10 ± 34.30
HDL-cholesterol (mg/dl) 35.23 ± 4.64 40.85 ± 9.85 33.46 ± 8.13
LDL-cholesterol (mg/dl) 90.00 ± 37.84 68.70 ± 39.79 74.54 ± 30.00

Table 2
Post meal plasma levels of MDA and lipid profile in both khat chewers and khat chewers and smokers
Control Khat chewers Khat chewers and smokers

Malondialdehyde (␮mol/l) 0.564 ± 0.176 0.678 ± 0.123∗ 0.804 ± 0.160∗∗


Triglycerides (mg/dl) 147.90 ± 71.87 134.50 ± 57.70 188.00 ± 69.00
Total cholesterol (mg/dl) 157.90 ± 41.28 164.00 ± 47.40 166.00 ± 38.20
HDL-cholesterol (mg/dl) 39.20 ± 9.34 41.00 ± 14.00 37.54 ± 6.95
LDL-cholesterol (mg/dl) 93.00 ± 24.40 92.60 ± 43.60 87.92 ± 36.99
∗ P < 0.02.
∗∗ P < 0.0001.
A. Al-Zubairi et al. / Journal of Ethnopharmacology 87 (2003) 3–9 5

Table 3
Plasma levels of MDA and lipid profile after 2 h of khat chewing in both tested groups
Control Khat chewers Khat chewers and smokers

Malondialdehyde (␮mol/l) 0.510 ± 0.151 0.640 ± 0.179∗ 0.763 ± 0.130∗∗


Triglycerides (mg/dl) 172.00 ± 87.00 128.80 ± 57.00 169.80 ± 62.90
Total cholesterol (mg/dl) 182.17 ± 39.18 150.80 ± 52.20 168.70 ± 41.20
HDL-cholesterol (mg/dl) 36.80 ± 8.80 42.70 ± 11.50 38.96 ± 6.22
LDL-cholesterol (mg/dl) 105.00 ± 27.50 82.60 ± 51.50 94.20 ± 39.90
∗ P < 0.03.
∗∗ P < 0.0002.

were lower in both khat chewers and khat chewers and smok- and LDL-cholesterol were non-significantly affected in both
ers by 24 and 17%, respectively. The levels of fasting plasma groups as compared to the control group.
HDL-cholesterol were not significantly different from that of Changes of the plasma levels of MDA and lipid profile
the control, although it was higher by 15% in the khat chew- at 2 h through khat session in both khat chewers and khat
ers and lower by 5% in the khat chewers and smokers group. chewers and smokers are highlight in Table 3. Like that of
Table 2 examines the changes of plasma MDA and lipid the post meal, plasma MDA at 2 h through khat session was
profile at post meal. Of all the factors tested only the post significantly higher in both khat chewers and khat chewers
meal plasma MDA was significantly higher in the khat chew- and smokers by 25.5 and 49%, respectively. Plasma triglyc-
ers group by approximately 21% and in the khat chewers and erides at 2 h through the khat session were non-significantly
smokers group by 43%. On the other hand, post meal plasma lower by 25% in khat chewers but were not much different
triglycerides was non-significant lower in the khat chewers in the khat chewers and smokers from that of the control
by 9% and non-significantly higher in the khat chewers and group. Plasma cholesterol were non-significantly lower by
smokers by 27% with respect to the control group. In con- 17% in khat chewers and by 7% in khat chewers and smok-
trast, post meal plasma total cholesterol, HDL-cholesterol, ers group. Similarly, the calculated plasma LDL-cholesterol

Fig. 1. Percentage increase of plasma MDA in both tested groups compared to the fasting levels.

Fig. 2. Percentage changes of MDA levels with respect to the control group.
6 A. Al-Zubairi et al. / Journal of Ethnopharmacology 87 (2003) 3–9

were non-significantly lower in both groups by 21 and 10%, glutathione (Ceriello, 2000). Moreover, the plasma concen-
respectively. On the other hand, plasma HDL-cholesterol at trations of protein-bound sulfhydryl groups, Vitamin C and
2 h through the khat session non-significantly higher by 16% uric acid as well as total radical-trapping antioxidant param-
in khat chewers and by 6% in khat chewers and smokers. eters were observed to decrease significantly during an oral
Fig. 1 highlight the percentage increase of plasma MDA glucose tolerance test in both diabetic and non-diabetic sub-
in both khat chewers and khat chewers and smokers at post jects (Ceriello et al., 1998b). Other reports have shown that
meal and 2 h through khat chewing with respect to their MDA increased in non-diabetic hyperlipidaemic patients
corresponding fasting levels. The data presented shows the compared to healthy subjects (Nacitarhan et al., 1995). Since
levels of MDA in the control group (non-khat chewers, the percentage increase of post meal MDA levels within
non-smokers) to increase by 11% at post meal (2 h from the each of the tested groups (∼29% in khat chewers and ∼45%
meal) and returns back to their levels of fasting, 4 h after the in khat chewers and smokers with respect to their corre-
meal. Whereas in both khat chewers and khat chewers and sponding fasting levels) were greater than that of the control
smokers, the levels of MDA though increased post meal by group. This would suggest the presence of other contributing
28.8 and 45%, respectively; the levels of MDA were only factors beside the meal-induced oxidative stress in both khat
dropped slightly at 2 h through the khat session by ∼7.5% chewers and khat chewers and smokers. In the case of the
in both groups. Fig. 2 depicts the percentage changes of khat chewers only, there may be an overall decrease in the
MDA levels at post meal and 2 h through khat chewing with antioxidant capacity as suggested by the observed reduction
respect to the corresponding control levels. This shows the of glutathione in khat fed rabbits (Farag et al., 1989).
levels of MDA to increase in both khat chewers and khat Analysis of the plasma MDA levels 2 h through the khat
chewers and smokers with respect to the control group at session revealed a further significant increase in both khat
fasting, post meal and 2 h through khat session; though the chewers (25.5%) and khat chewers and smokers (50%) (P <
increase is much significant at post meal and 2 h through 0.03 and 0.0002, respectively) (Fig. 2). This might also be
khat session. The levels of MDA were also observed to be partly due to meal-induced oxidative stress as a consequence
much higher in the khat chewers and smokers when com- of the decrease motility of the food and delayed absorption
pared with the khat chewers only. The increase was about (Heymann et al., 1995) caused by khat chewing. Alterna-
two-folds at post meal and at 2 h through khat session. tively, the increased plasma MDA after 2 h of khat chewing
might be due to the reported increase of thyroid hormones
(Islam et al., 1990), which have been proved to induce an
4. Discussion increase in plasma MDA (Seven et al., 1996).
Since the levels of plasma MDA were not further in-
In this study plasma MDA, the most frequently used creased 2 h through the khat session than those levels of
marker of lipid peroxidation (Janero, 1990; Gutteridge and post meal may suggest no additive effect for khat chew-
Halliwell, 1990) and a biomarker of oxidative stress (Nielsen ing. On calculating the percentage change with respect to
et al., 1997), have been used to investigate the effect of the corresponding fasting levels, it becomes evident that
regular khat chewing and the combination of khat chew- in the case of the control (non-khat chewers, non-smokers)
ing and smoking on oxidative stress/free radical activity. group the level of MDA falls back to the base-line level of
Our results showed the fasting plasma levels of MDA to the fasting sample (Fig. 1). Whereas in both khat chewers
be non-significantly increased by 4% in khat chewers and and khat chewers and smokers, the MDA levels dropped
by 9.2% in khat chewers and smokers as compared to the by ∼7.5%. This may suggest that khat chewing may not
plasma levels of MDA in the control (non-khat chewers and provoke lipid peroxidation, and hence may have some
non-smokers) group. antioxidative property. This would follow, since khat has
In contrast to the non-significant differences in the fasting been known to contain polyphenolic (proanthocynidines)
plasma MDA levels, post meal MDA levels in khat chewers constituents that have emerged recently to play a role as
were significantly increased (P < 0.02) by 21% when com- antioxidants (Hagerman et al., 1998; Koga et al., 1999).
pared to the corresponding control group. These levels were Smoking has been suggested to be one of the promi-
even greater (increase of 42%) in the group that regularly nent risk factors for increased lipid peroxidation, because of
chewed khat and smoked (P < 0.0001). This significant the presence of free radicals in cigarette smoke (Halliwell
increase in the post meal MDA levels in both groups could and Gutteridge, 1989), that increase plasma MDA. Previ-
be attributed partially to the meal-induced oxidative stress. ous studies of smoking and oxidative stress in humans have
This is observed on examining the changes of plasma MDA been difficult to interpret. Harats et al. (1989) and Pre’ and
levels within the control group, where an 11% increase was Le Floch (1990) found no significant differences between
observed 2 h following the meal (Fig. 1). Recent studies smokers and non-smokers in the levels of thiobarbituric acid
have reported an increase in the oxidative stress following reacting substances in freshly prepared plasma. Whereas,
meals in normal subjects (Ceriello et al., 1998a; Ursini et al., other groups have reported significantly higher levels of
1998) with consumption of antioxidant defenses (Ceriello thiobarbituric acid reacting substances in smokers compared
et al., 1998a; Ceriello, 2000) particularly reduction in plasma to non-smokers (Kalra et al., 1991; Bridges et al., 1993).
A. Al-Zubairi et al. / Journal of Ethnopharmacology 87 (2003) 3–9 7

Plasma MDA levels were also found to be 10% greater in group (khat chewers and smokers) may be attributed to the
smokers compared to non-smokers (Nielsen et al., 1997). opposing effects of khat and smoking on plasma triglyceride
The latter findings were further confirmed by animal work levels.
of Helen and Vijayammal (1997) who found increased con- Total cholesterol in this study tended to be non-signifi-
centrations of MDA, conjugated dienes and hydroperoxides cantly affected in both khat chewers and khat chewers and
in rats exposed to cigarette smoke. Our results may indi- smokers groups compared with the corresponding control
rectly tend to support findings of smoking increasing plasma groups at fasting, post meal or after 2 h of the khat chew-
MDA levels. This is evident by the higher increase of MDA ing. This observed decrease, though non-significant, in
in the khat chewers and smokers group. Whether khat chew- serum cholesterol concentration in khat chewers may be at-
ing helps to reduce the risk of increased lipid peroxidation in tributed to the increase in c-AMP that has inhibitory effect
the khat chewers and smokers group cannot be determined on cholesterol synthesis (Mayes, 2000). The stimulation
from this study. This is because of the difficulty in finding of ␤-adrenergic receptors by the amphetamine-like effect
smokers that do not chew khat in the Yemeni population. of cathinone (Tariq et al., 1989) results in activation of
Since the majority of people tend to smoke only when they adenylyl cyclase and consequently increased conversion of
chew khat. ATP to c-AMP (Mayes, 2000), in addition to its stimulatory
Fasting serum triglycerides were found to be non-signifi- effect on adrenocorticotrophic hormone (ACTH), that have
cantly increased in both khat chewers (9%) and in khat been reported to be increased in rabbits given Catha edulis
chewers and smokers (13%) compared to the control extract (Ahmed and El-Qirbi, 1993). ACTH is also believed
group. Other studies have shown fasting triglycerides to be to be mediated by the activation of adenylyl cyclase with
significantly increased in smokers by 9.1% (Craig et al., subsequent increase in c-AMP concentration.
1989) and by 12–15.6% (Hughes et al., 1998) as compared HDL-cholesterol in khat chewers was found to be
to non-smokers. Fasting samples of khat chewers in both non-significantly higher at fasting, post meal and 2 h of khat
groups represent an 18 h sample after the start of the last chewing when compared with the corresponding control
khat session and this would suggest that the plasma cathi- group. Calculated serum levels of LDL-cholesterol of khat
none should have been cleared 9 h prior to this sampling chewers were non-significantly lower with respect to the
according to the study of Widler et al. (1994). The latter control group in the fasting and after 2 h of khat chewing.
study reported maximal plasma concentration of cathinone These findings were similar to that observed by Ramadan
reached at 1.5–2.5 h with a half-life in plasma of 4 h as et al. (1979) who reported that total cholesterol, ␣- and
confirmed later on by Halket et al. (1995) who stated that ␤-lipoproteins were not greatly affected by khat consump-
the peak levels of plasma cathinone being reached after tion. The observed reciprocal relationship between plasma
1.5–3.5 h of the start of khat chewing and declined rapidly HDL-cholesterol and triglycerides in khat chewers, at post
by 7.5 h. This would, therefore, suggest that cathinone, the meal and 2 h through khat chewing, are in support of re-
main active constituent of khat leaves, does not contribute cent data demonstrating HDL-cholesterol concentrations
to the observed results on fasting triglycerides. to vary reciprocally with plasma triglycerides concentra-
On the other hand, post meal serum triglycerides of khat tion, and directly with lipoprotein lipase (Mayes, 2000).
chewers were non-significantly lower by 9% as compared This could be explained by the effect of cathinone and its
to the control group. This decrease in the levels of plasma amphetamine-like effect on adrenergic receptors increasing
triglycerides were even more prominent and marked (25%), c-AMP that in turn stimulate lipoprotein lipase (Ramadan
though not significant, after 2 h of the start of khat chewing et al., 1979).
with respect to the control group. This lowering effect of khat HDL-cholesterol in the khat chewers and smokers group
on triglycerides can be explained by the amphetamine-like were seen to be non-significantly affected compared with
sympathomimetic effects of cathinone, which favors lipoly- the control group, being slightly lower at fasting and at post
sis mediated through stimulation of ␤-adrenergic receptors meal while increased after 2 h of khat chewing. Similar re-
(Tariq et al., 1989). In this context, cathinone was also found ductions in HDL-cholesterol have been observed in smokers
to increases the metabolic rate and oxygen consumption of only (Craig et al., 1989; Hughes et al., 1998). The calculated
rats (Knoll, 1979) and enhances lipolysis in vitro and in vivo LDL-cholesterol was not affected in the khat chewers and
(Nencini, 1980). In contrast, post meal plasma triglycerides smokers to the extent seen in the khat chewers only. This
were non-significantly higher by 27% in the khat chewers could be explained by the opposing effects of khat chewing
and smokers group. This is in line with previous findings and smoking on plasma lipids or due to the pattern of smok-
showing that smokers in whom the delivery of fatty acids ing and the number of cigarettes smoked. The disturbance
to the liver is stimulated are likely to have a high levels of of plasma lipid levels found in smokers only was attributed
VLDL synthesis and triglycerol concentration (Craig et al., by many authors to the dietary differences between smokers
1989; Cade, 1989). Interestingly, 2 h after the start of khat and non-smokers (Craig et al., 1989; Cade, 1989; Freeman
chewing, serum triglycerides of khat chewers and smokers and Packard, 1995). Smoking was demonstrated to have
group drops back to the same level as that of the control a strong independent influence on HDL-cholesterol (Craig
group. This normalization of the plasma triglycerides in this et al., 1989) and the evidence for this comes from smoking
8 A. Al-Zubairi et al. / Journal of Ethnopharmacology 87 (2003) 3–9

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